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PubMed2005

Abnormalities in cartilage and bone development in the Apert syndrome FGFR2(+/S252W) mouse.

Apert syndrome is an autosomal dominant disorder characterized by malformations of the skull, limbs and viscera. Two-thirds of affected individuals have a S252W mutation in fibroblast growth factor receptor 2 (FGFR2). To study the pathogenesis of this condition, we generated a knock-in mouse model with this mutation. The Fgfr2(+/S252W) mutant mice have abnormalities of the skeleton, as well as of other organs including the brain, thymus, lungs, heart and intestines. In the mutant neurocranium, we found a midline sutural defect and craniosynostosis with abnormal osteoblastic proliferation and differentiation. We noted ectopic cartilage at the midline sagittal suture, and cartilage abnormalities in the basicranium, nasal turbinates and trachea. In addition, from the mutant long bones, in vitro cell cultures grown in osteogenic medium revealed chondrocytes, which were absent in the controls. Our results suggest that altered cartilage and bone development play a significant role in the pathogenesis of the Apert syndrome phenotype.

Acrocephalosyndactylia↗
PubMed2000

Integration of FGF and TWIST in calvarial bone and suture development.

Mutations in the FGFR1-FGFR3 and TWIST genes are known to cause craniosynostosis, the former by constitutive activation and the latter by haploinsufficiency. Although clinically achieving the same end result, the premature fusion of the calvarial bones, it is not known whether these genes lie in the same or independent pathways during calvarial bone development and later in suture closure. We have previously shown that Fgfr2c is expressed at the osteogenic fronts of the developing calvarial bones and that, when FGF is applied via beads to the osteogenic fronts, suture closure is accelerated (Kim, H.-J., Rice, D. P. C., Kettunen, P. J. and Thesleff, I. (1998) Development 125, 1241-1251). In order to investigate further the role of FGF signalling during mouse calvarial bone and suture development, we have performed detailed expression analysis of the splicing variants of Fgfr1-Fgfr3 and Fgfr4, as well as their potential ligand Fgf2. The IIIc splice variants of Fgfr1-Fgfr3 as well as the IIIb variant of Fgfr2 being expressed by differentiating osteoblasts at the osteogenic fronts (E15). In comparison to Fgf9, Fgf2 showed a more restricted expression pattern being primarily expressed in the sutural mesenchyme between the osteogenic fronts. We also carried out a detailed expression analysis of the helix-loop-helix factors (HLH) Twist and Id1 during calvaria and suture development (E10-P6). Twist and Id1 were expressed by early preosteoblasts, in patterns that overlapped those of the FGF ligands, but as these cells differentiated their expression dramatically decreased. Signalling pathways were further studied in vitro, in E15 mouse calvarial explants. Beads soaked in FGF2 induced Twist and inhibited Bsp, a marker of functioning osteoblasts. Meanwhile, BMP2 upregulated Id1. Id1 is a dominant negative HLH thought to inhibit basic HLH such as Twist. In Drosophila, the FGF receptor FR1 is known to be downstream of Twist. We demonstrated that in Twist(+/)(-) mice, FGFR2 protein expression was altered. We propose a model of osteoblast differentiation integrating Twist and FGF in the same pathway, in which FGF acts both at early and late stages. Disruption of this pathway may lead to craniosynostosis.

Acrocephalosyndactylia↗
PubMed2002

Characterization of a dominant negative C. elegans Twist mutant protein with implications for human Saethre-Chotzen syndrome.

Twist is a transcription factor that is required for mesodermal cell fates in all animals studied to date. Mutations of this locus in humans have been identified as the cause of the craniofacial disorder Saethre-Chotzen syndrome. The Caenorhabditis elegans Twist homolog is required for the development of a subset of the mesoderm. A semidominant allele of the gene that codes for CeTwist, hlh-8, has defects that occur earlier in the mesodermal lineage than a previously studied null allele of the gene. The semidominant allele has a charge change (E29K) in the basic DNA-binding domain of CeTwist. Surprisingly, the mutant protein retains DNA-binding activity as both a homodimer and a heterodimer with its partner E/Daughterless (CeE/DA). However, the mutant protein blocks the activation of the promoter of a target gene. Therefore, the mutant CeTwist may cause cellular defects as a dominant negative protein by binding to target promoters as a homo- or heterodimer and then blocking transcription. Similar phenotypes as those caused by the E29K mutation were observed when amino acid substitutions in the DNA-binding domain that are associated with the human Saethre-Chotzen syndrome were engineered into the C. elegans protein. These data suggest that Saethre-Chotzen syndrome may be caused, in some cases, by dominant negative proteins, rather than by haploinsufficiency of the locus.

Acrocephalosyndactylia↗
PubMed2005

Cbl-mediated ubiquitination of alpha5 integrin subunit mediates fibronectin-dependent osteoblast detachment and apoptosis induced by FGFR2 activation.

Fibroblast growth factor receptor signaling is an important mechanism regulating osteoblast function. To gain an insight into the regulatory role of FGF receptor-2 (FGFR2) signaling in osteoblasts, we investigated integrin-mediated attachment and cell survival in human calvarial osteoblasts expressing activated FGFR2. FGFR2 activation reduced osteoblast attachment on fibronectin. This was associated with reduced expression of the alpha5 integrin subunit normally expressed in human calvarial osteoblasts in vivo. Treatment with lactacystin, a potent inhibitor of proteasome, restored alpha5 integrin levels in FGFR2 mutant osteoblasts. Immunoprecipitation analysis showed that alpha5 integrin interacts with both the E3 ubiquitin ligase Cbl and ubiquitin. Immunocytochemistry revealed that alpha5 integrin colocalizes with FGFR2 and Cbl at the leading edge in membrane ruffle regions. Transfection with the 70Z-Cbl mutant lacking the RING domain required for Cbl-ubiquitin interaction, or with the G306E Cbl mutant that abolishes the binding ability of Cbl phosphotyrosine-binding domain restored alpha5 integrin levels. This suggests that Cbl-mediated ubiquitination plays an essential role in alpha5 integrin proteasome degradation induced by FGFR2 activation. Reduced alpha5 integrin expression was associated with an increased Bax/Bcl-2 ratio and increased caspase-9 and -3 activities in FGFR2 mutant osteoblasts. Forced expression of alpha5 integrin rescued cell attachment and corrected both the Bax/Bcl-2 ratio and caspase-3 and caspase-9 activities in FGFR2 mutant osteoblasts. We show that Cbl recruitment induced by FGFR2 activation triggers alpha5 integrin degradation by the proteasome, which results in reduced osteoblast attachment on fibronectin and caspase-dependent apoptosis. This identifies a functional role of the alpha5 integrin subunit in the induction of apoptosis triggered by FGFR2 activation in osteoblasts, and reveals that a Cbl-dependent mechanism is involved in the coordinated regulation of cell apoptosis induced by alpha5 integrin degradation.

Acetylcysteine↗
PubMed2005

Management of hearing loss in Apert syndrome.

BACKGROUND: Apert syndrome is one of the craniosynostosis syndromes, with a birth prevalence estimated to be between 9.9 and 15.5/million, and accounts for 4.5 per cent of craniosynostoses. Although conductive hearing loss is common in Apert syndrome there are contradicting reports regarding the cause of this hearing loss. There is also no detailed information available on the management of hearing loss in Apert syndrome. MATERIALS AND METHODS: A retrospective analysis of case notes of Apert syndrome patients seen between 1970 and 2003 at Great Ormond Street Children's Hospital, London, was undertaken. RESULTS: Seventy case notes were obtained. The incidence of congenital hearing impairment was between 3 and 6 per cent. Almost all patients had otitis media with effusion (glue ear), which tended to persist into adult life. More than 56 per cent of cases developed permanent conductive hearing loss by 10-20 years. Repeated grommet insertion was common; even though 35 per cent had trouble with ear discharge and persistent conductive hearing loss. Statistically, grommets made no difference to the risk of developing permanent hearing loss. CONCLUSION: This study, of the largest number of Apert syndrome cases assembled to date, showed that early optimization of hearing with possible hearing aids needs to be considered. Repeated grommet insertion does not help in optimizing hearing, especially if ear discharge complicates the picture.

Acrocephalosyndactylia↗
PubMed2006

Clinical and radiographic presentation and preparation of the prototyping model for pre-surgical planning in Apert's syndrome.

Acrocephalosyndactyly, or Apert's syndrome, described nearly a century ago, is a craniofacial dysostosis, an autosomal dominant condition characterized by severe development disturbances of the craniofacial region including bilateral coronal synostosis associated with midface hypoplasia, exophthalmia, hypertelorism, symmetric syndactyly of the hands and feet, cone-shaped calvarium, pharyngeal attenuation and malocclusion. The aim of this study was to assess clinical and computed tomography (CT) imaging patterns of a non-operated patient with Apert's syndrome, correlating the cranium, face and the skull base bone abnormalities. Three-dimensional images were generated from spiral CT scans in order to produce a prototyping model in polyamide material. Clinical examination determined that syndactyly of the hands and feet, pseudocleft in the midline palate and midface hypoplasia were present. The surgical model allowed the analysis of some abnormalities regarding to calvaria morphology, nasal bones and maxilla, improving the criteria for a case diagnosis and surgical plan.

Acrocephalosyndactylia↗
PubMed2001

Increased expression of protein kinase Calpha, interleukin-1alpha, and RhoA guanosine 5'-triphosphatase in osteoblasts expressing the Ser252Trp fibroblast growth factor 2 receptor Apert mutation: identification by analysis of complementary DNA microarray.

Apert (Ap) syndrome is a craniofacial malformation characterized by premature fusion of cranial sutures (craniosynostosis). We previously showed that the Ser252Trp fibroblast growth factor receptor 2 (FGFR-2) mutation in Ap syndrome increases osteoblast differentiation and subperiosteal bone matrix formation, leading to premature calvaria ossification. In this study, we used the emerging technology of complementary DNA (cDNA) microarray to identify genes that are involved in osteoblast abnormalities induced by the Ser252Trp FGFR-2 mutation. To identify the signaling pathways involved in this syndrome, we used radioactively labeled cDNAs derived from two sources of cellular messenger RNAs (mRNAs) for hybridization: control (Co) and mutant Ap immortalized osteoblastic cells. Among genes that were differentially expressed, protein kinase Ca (PKC-alpha), interleukin-1alpha (IL-1alpha), and the small guanosine-5'-triphosphatase (GTPase) RhoA were increased in FGFR-2 mutant Ap cells compared with Co cells. The validity of the hybridization array was confirmed by Northern blot analysis using mRNAs derived from different cultures. Furthermore, immunochemical and Western blot analyses showed that mutant Ap cells displayed increased PKC-alpha, IL-1alpha, and RhoA protein levels compared with Co cells. Treatment of Co and Ap cells with the PKC inhibitor calphostin C decreased IL-1alpha and RhoA mRNA and protein levels in Ap cells, indicating that PKC is upstream of IL-1alpha and RhoA. Moreover, SB203580, a specific inhibitor of p38 mitogen-activated protein kinase (MAPK), and PD-98059, a specific inhibitor of MAPK kinase (MEKK), also reduced IL-1alpha and RhoA expression in Ap cells. These data show that the Ser252Trp FGFR-2 mutation in Ap syndrome induces constitutive overexpression of PKC-alpha, IL-1alpha, and small GTPase RhoA, suggesting a role for these effectors in osteoblast alterations induced by the mutation. The cDNA microarray technology appears to be a useful tool to gain information on abnormal gene expression and molecular pathways induced by genetic mutations in bone cells.

Acrocephalosyndactylia↗
PubMed2001

Role of N-cadherin and protein kinase C in osteoblast gene activation induced by the S252W fibroblast growth factor receptor 2 mutation in Apert craniosynostosis.

Apert (Ap) syndrome is characterized by premature cranial suture ossification caused by fibroblast growth factor receptor 2 (FGFR-2) mutations. We studied the role of cadherins and signaling events in the phenotypic alterations induced by the Ap FGFR-2 S252W mutation in mutant immortalized fetal human calvaria osteoblasts. The FGFR-2 mutation caused increased expression of the osteoblast markers alkaline phosphatase (ALP), type 1 collagen (COLIA1), and osteocalcin (OC) in long-term culture. The mutation also increased cell-cell aggregation, which was suppressed by specific neutralizing anti-N- and anti-E-cadherin antibodies. Mutant osteoblasts showed increased N- and E-cadherin, but not N-cell adhesion molecule (N-CAM) messenger RNA (mRNA) and protein levels. This was confirmed in vivo by the abundant immunoreactive N- and E-cadherins in preosteoblasts in the Ap suture whereas N-CAM and alpha- and beta-catenins were unaffected. Neutralizing anti-N-cadherin antibody or N-cadherin antisense (AS) oligonucleotides but not anti-E-cadherin antibody or AS reduced ALP activity as well as ALP, COLIA1, and OC mRNA overexpression in mutant osteoblasts. Analysis of signal transduction revealed increased phospholipase Cgamma (PLCgamma) and protein kinase Calpha (PKCalpha) phosphorylation and increased PKC activity in mutant cells in basal conditions. Inhibition of PKC by calphostin C or the PKCalpha-specific inhibitor Gö6976 suppressed the increased N-cadherin mRNA and protein levels as well as the overexpression of ALP, COLIA1, and OC mRNA in mutant cells. Thus, N-cadherin plays a role in the activation of osteoblast differentiation marker genes in mutant osteoblasts and PKCalpha signaling appears to be involved in the increased N-cadherin and osteoblast gene expression induced by the S252W FGFR-2 mutation in human osteoblasts.

Acrocephalosyndactylia↗
PubMed2005

Mutations in snail family genes enhance craniosynostosis of Twist1 haplo-insufficient mice: implications for Saethre-Chotzen Syndrome.

In Drosophila, mutations in the Twist gene interact with mutations in the Snail gene. We show that the mouse Twist1 mutation interacts with Snai1 and Snai2 mutations to enhance aberrant cranial suture fusion, demonstrating that genetic interactions between genes of the Twist and Snail families have been conserved during evolution.

Acrocephalosyndactylia↗
PubMed2001

Neuropsychological and phonological evaluation in the Apert's syndrome: study of two cases.

This study evaluated two cases of Apert's syndrome, through phonological, cognitive, and neuropsychological instruments and correlated the results to complementary exams. In short, this study reveals the necessity of application of neuropsychological, cognitive and phonological evaluation and correlation of the results with complementary testings because significant differences can be present in the Apert's syndrome.

Acrocephalosyndactylia↗
PubMed2005

Apert syndrome: factors involved in the cognitive development.

Apert syndrome is characterized by craniosynostosis, symmetric syndactyly and other systemic malformations, with mental retardation usually present. The objective of this study was to correlate brain malformations and timing for surgery with neuropsychological evaluation. We also tried to determine other relevant aspects involved in cognitive development of these patients such as social classification of families and parents education. Eighteen patients with Apert syndrome were studied, whose ages were between 14 and 322 months. Brain abnormalities were observed in 55.6% of them. The intelligence quotient or developmental quotient values observed were between 45 and 108. Mental development was related to the quality of family environment and parents education. Mental development was not correlated to brain malformation or age at time of operation. In conclusion, quality of family environment was the most significant factor directly involved in mental development of patients with Apert syndrome.

Acrocephalosyndactylia↗
PubMed2003

Pfeiffer Syndrome type 2--case report.

OBJECTIVE: To report on a case of Pfeiffer Syndrome, with a discussion of the diagnostic characteristics and features of disease types and the differential diagnosis. DESCRIPTION: The authors describe a newborn with cloverleaf skull, extreme bilateral exorbitism and choanal atresia, partial syndactyly of the second and third toes and broad medially-deviated big toes. The case reported was Pfeiffer Syndrome type 2, which usually has a poor prognosis. COMMENTS: Pfeiffer Syndrome is a clinically variable disorder and consists of an autosomal dominantly-inherited osteochondrodysplasia with craniosynostosis. It has been divided into three types. Type 1 is commonly associated with normal intelligence and generally good outcome. Types 2 and 3 generally have severe neurological compromise, poor prognosis, early death and sporadic occurrence. Potential for prolonged useful survival outcome can be achieved in some cases with early aggressive medical and surgical management according to recent literature.

Acrocephalosyndactylia↗
PubMed2004

Computed tomography assessment of Apert syndrome.

Apert syndrome, or acrocephalosyndactyly type I, is a craniofacial dysostosis, an autosomal dominant condition characterized by severe developmental disturbances of the craniofacial region including bilateral coronal synostosis associated with midface hypoplasia, exophthalmia, hypertelorism, and symmetric syndactyly of the hands and feet. The aim of this study is to assess the clinical and computed tomography imaging patterns of non-operated patients with Apert syndrome, correlating the bone abnormalities of the cranium, face and the skull base. The study population consisted of 5 patients with Apert syndrome. As part of the craniofacial assessment of the imaging center's routine, all patients underwent clinical evaluation and CT (computed tomograph) exam. Three-dimensional images were generated from helical CT scans, using an independent workstation, to evaluate the craniofacial abnormalities of the syndrome. Clinical exam determined that syndactyly of the hands and feet, pseudocleft in the midline palate and midface hypoplasia were features observed in all of the Apert patients. 3D-CT showed that some abnormalities such as bilateral coronal synostosis, calvarial midline defect and reduction in the antero-posterior dimension of the anterior, medial and posterior cranial fossae were present in all cases. In conclusion, the correlation of clinical and CT imaging findings can be useful to assess the main features observed in Apert patients, improving the criteria for examining the patient and diagnosing this condition, and contributing to the therapeutic planning and surgical follow-up.

Acrocephalosyndactylia↗
PubMed2004

Clinical findings in four Brazilian families affected by Saethre-Chotzen syndrome without TWIST mutations.

OBJECTIVE: To analyze the dysmorphological variability and to investigate the presence of mutations in the exon 1 of TWIST gene using direct sequencing in Brazilian families presenting with Saethre-Chotzen Syndrome (SCS). METHODS: Four families with 24 patients diagnosed as having features of SCS were studied. Phenotypic characteristics of all patients were inventoried. The investigation protocol included anamnesis, dysmorphological examination, abdominal ultrasound, spine and cranium x-ray, chromosomal analysis on GTG banding, and screening for mutations in the exon 1 of TWIST gene. RESULTS: Frequent facial features included brachycephaly (24 of 24), facial asymmetry (20 of 24), prominent ears crus (15 of 24), low-set ears (14 of 24), maxillary hypoplasia (13 of 24), prominent nasal bridge (13 of 24), ptosis of the eyelids (12 of 24), and low-set frontal hairline (12 of 24). Limb abnormalities such as partial hand cutaneous syndactyly (18 of 24), clinodactyly (13 of 24), and broad great toes (13 of 24), and partial cutaneous syndactyly of the feet (9 of 24) were also detected. Among radiological findings were relevant bicoronal (eight of nine) and unicoronal (one of nine) craniosynostosis, digital impressions (eight of nine), bilateral parietal foramina (two of nine), partial fusion 1 and 2 degrees costal arches (two of nine) and bifid spine on lumbar vertebra (two of nine). GTG-banding chromosomal analyses were normal. No TWIST gene mutations were found. CONCLUSIONS: Affected individuals in these four SCS families may carry mutations in other genes of the same developmental pathway. Considering the complexity of the genes involved in skull-limbs development, an accurate dysmorphological evaluation in patients with SCS and their families is especially important for genetic counseling.

Acrocephalosyndactylia↗
PubMed2006

Dual segmental distraction osteogenesis of the midface in a patient with Apert syndrome.

OBJECTIVE: To present orthodontic treatment combined with dual segmental distraction osteogenesis in a patient with Apert syndrome. PATIENT: A 15-year-old boy exhibited severe midfacial hypoplasia with retruded and hypoplastic maxilla and anterior open bite. The patient was treated with a rigid external distraction II system for distraction osteogenesis, a preadjusted edgewise appliance, and a modified maxillary protraction headgear. The concave profile with midfacial hypoplasia was improved. A tight occlusal relationship between maxillary and mandibular teeth was achieved. Postoperative treatment results have been stable for 1 year.

Acrocephalosyndactylia↗
PubMed2006

Q289P mutation in FGFR2 gene causes Saethre-Chotzen syndrome: some considerations about familial heterogeneity.

OBJECTIVE: To describe the first report on a three-generation family presenting typical features of Saethre-Chotzen syndrome, in which the Q289P mutation in the FGFR2 gene was detected. DESIGN: Dysmorphological evaluation was performed by a clinical geneticist. Direct sequencing of the polymerase chain reaction-amplified coding region of TWIST and screening for the P250R mutation in the FGFR3 gene were performed. Exons IIIa and IIIc of FGFR2 were sequenced also. The mutation was confirmed by both restriction-enzyme digestion and allelic-specific polymerase chain reaction. RESULTS: Neither TWIST gene analysis nor analysis of the P250R mutation on gene FGFR3 showed mutation within the coding sequence. A nucleotide change from CAG to CCG in exon IIIa of the FGFR2 gene that caused a Q289P mutation was detected, although exon IIIc in the propositus was normal. These same results were detected in his mother, but no other members of the kindred presented clinical features consistent with Saethre-Chotzen syndrome. CONCLUSIONS: This mutation was previously reported in individuals with Crouzon and Jackson-Weiss syndromes. The FGFR2 mutation in the family with Saethre-Chotzen syndrome herein reported reinforces the idea of an interaction among TWIST and FGFR genes during development. Absence of the Q289P mutation in some affected individuals in this family is discussed.

Acrocephalosyndactylia↗
PubMed1992

Cranio-orbito-zygomatic measurements from standard CT scans in unoperated Crouzon and Apert infants: comparison with normal controls.

Cranio-orbito-zygomatic measurements taken from standard axial computed tomographic (CT) scans of unoperated patients with Crouzon syndrome (6 males, 14 females) and Apert syndrome (6 males, 10 females) under 1 year of age were compared to each other and to normal controls (40 males, 35 females). Fifteen cranio-orbito-zygomatic variables were measured and repeated. Means and standard deviations were computed for each sex, and means were pooled since they were not significantly different. Correlation coefficients for repeat measures (intra-observer error) of each variable showed good reproducibility. Only the lateral orbital wall angle differed between the syndromes (p = .034), suggesting that upper facial differences (as measured by these variables) do not manifest themselves at this young age. All measurements for both syndromes, except one, were outside the 95 percent confidence range for age-matched controls. Measurements taken from standard CT scans provide an objective comparison between specific syndromes and the normal population.

Acrocephalosyndactylia↗