Crouzon Patients Research Articles

Facial Malformation in Crouzon's Syndrome Is Consistent with Cranial Base Development in Time and Space.

In Crouzon's syndrome, cranial base deformities begin sequentially in the anterior cranial fossa initially, and later to the posterior cranial base. Facial characteristics are likely related to cranial base development. The temporal correlation between cranial base development and facial features is in need of clarification in Crouzon's patients, to clarify initial sites of deformity, which may impact surgical decision making. Thirty-six computed tomography scans of unoperated Crouzon's syndrome patients and 54 controls were included and divided into 5 age-subgroups. All the planes used for analysis were set as perpendicular to a defined "midplane" to offset the confounding factor caused by potential asymmetry. The angle between Sella-Nasion plane and Frankfort horizontal plane was significantly increased before 6 months of age (P = 0.014), with an average 70% (P < 0.001) increase ultimately into adulthood. The angle between SN and maxillary plane and the angle between Sella-Nasion and occlusal planes increased consistently through infancy to adulthood (124% and 42%, respectively, both P < 0.001). The relative angle of mandibular plane to Frankfort horizontal plane increased before 6 months (28%, P = 0.007) with a peak timeframe from 2 to 18 years. Facial lateral curvature related measurements indicate the whole face is inclined posteriorly and inferiorly direction in relation to the anterior cranial base. Crouzon's facial malformation development is synchronous and positionally correlational with cranial base deformity. It transmitted from orbit to mandible, with the most evident morphologic changes are in the orbit and midface.

0890 INDIVIDUALIZED THERAPY FOR TREATING OBSTRUCTIVE SLEEP APNEA IN PEDIATRIC CROUZON SYNDROME PATIENTS

Pediatric patients with Crouzon syndrome have great possibilities in suffering from obstructive sleep apnea (OSA), which is mainly due to midfacial hypoplasia and facial deformities. For most patients, a multi-disciplinary and sequential treatment plan is necessary to make for Crouzon syndrome often has different phenotypes of different severity in OSA and facial deformities. Typical patients were selected in this study to illustrate the necessity of individualized therapy for treating OSA. In the study, four Crouzon syndrome children of different severity in suffering from OSA and maxillofacial deformities were introduced. Detailed information in individualized treatment options was given including clinical manifestations, radiological findings, polysomnography detectings and treatment combinations. Based on the above findings, different but effective treatment options for these children’s OSA problems were adopted, either by surgeries including distraction osteogenesis and craniomaxillofacial surgeries with or without tonsillectomy, or by noninvasive continuous positive airway pressure (CPAP) therapy. Patient 1 was performed with LeFort IIIosteotomy and external distraction osteogenesis. Patient 2 was given LeFort IIIosteotomy and external distractor fixation and concurrent bilateral mandibular body osteotomy and internal distractor fixation for bimaxillary distraction. Patient 3 received LeFort I osteotomy for maxillary advancement with concurrent bilateral tonsillectomy. Differently, patient 4 with mild OSA disturbance adopted initial continuous positive airway pressure (CPAP) with good adherence and body development. Six years later, he began orthodontic treatment for preparing for orthognathic surgery. Recently bimaxillary surgery was performed on him to enlarge upper airway anatomically as well as improve facial profile. Follow-up studies showed problems of OSA and nocturnal hypoxia of those four patients were all alleviated greatly, as well as maxillofacial deformities. Combined with preoperative and postoperative orthodontics, patient 1 and 4 also got optimal results in better facial profile and dental occlusion. Thus, given Crouzon patients had great possiblilities in suffering from OSA and hypoxia problems, individualized therapy should be made and performed carefully to obtain optimized treatment results based on adequate clinical evaluations and patients’ conditions including age, disease severity and esthetic considerations. This work was supported by the National Natural Science Foundation of China (Grant number: 81470786).

The Phenotypes of Spheno-Occipital Synchondrosis in Patients With Crouzon Syndrome.

To characterize the phenotypes of spheno-occipital synchondrosis (SOS) in Chinese patients with Crouzon syndrome. Twelve patients with Crouzon syndrome were included in this retrospective study, and were divided into 2 groups. The first group included 5 patients (5-7-year old), whereas 7 patients were included in the second group (8-11-year old). Two age- and sex-matched control groups were constituted for comparison. All patients and controls were underwent preoperative computed tomography examinations of the craniofacial area, and the three-dimensional skull models, sagittal, and axial images were reconstructed. The density of the SOS region was also calculated. The SOS was partially closed in the first Crouzon patients group, whereas the SOS was open in control groups. The SOS was completely fused SOS in the second Crouzon patients group, whereas the SOS was open or partially closed in control groups. There also were short and hypoplastic sphenoid bone in both Crouzon groups when compared with controls. In addition, the average density of SOS in patients with Crouzon syndrome was higher than the control groups (P <0.01). The SOS begins to prematurely fuse in Chinese patients with Crouzon syndrome, and there are short and hypoplastic sphenoid bone in these patients. Although a definitive role of prematurely fused SOS in Crouzon syndrome cannot be drawn, our finds provide important clues into the mechanisms, and potentially provide a treatment target for midfacial and cranial vault hypoplasia in Crouzon patients.

Atypical post-adenoidectomy Grisel's syndrome in Crouzon child with kyphotic skull base

Crouzon syndrome is characterized by abnormal craniofacial growth due to craniosynostosis. Skull base may also be involved in the pattern of malformations. Grisel's syndrome, an inflammation-mediated atlanto-axial instability occurs rarely in children after adenoidectomy. We report a 9-year-old female Crouzon patient, without vertebral anomalies, who developed severe torticollis few days after adenoid curettage. A deformity of the skull base alone might have induced an irregular arrangement of the craniocervical junction elements, thus increasing the susceptibility to cervical spine complications.

Patterns of Tooth Agenesis in Patients with Crouzon or Apert Syndrome

Dental agenesis is the most common anomaly of dental development and can be a component of a congenital syndrome. The purpose of this study was to evaluate the prevalence of agenesis and to describe patterns of tooth agenesis in patients with Crouzon or Apert syndrome compared with nonsyndromic controls. Longitudinal records of 67 patients with Crouzon syndrome (n = 39) or Apert syndrome (n = 28) from the Erasmus Medical Centre were examined. Syndromic patients were compared with patients in a nonsyndromic control group (n = 284). Prevalence of tooth agenesis in patients with Crouzon syndrome (35.9%) and patients with Apert syndrome (46.4%) was significantly higher than the prevalence in control subjects (27.5%) (P < .005). In all groups third molars were the most likely to be agenetic. Tooth agenesis excluding third molars was significantly higher in syndromic patients than in control subjects (P < .001). Bilateral agenesis of mandibular second premolars occurred significantly more often in patients with Crouzon and Apert syndrome than in control subjects (P < .001). Tooth agenesis is more prevalent in patients with Crouzon or Apert syndrome than in control subjects. Tooth agenesis and mandibular symmetrical patterns of second premolar agenesis are more prevalent in syndromic patients.

Patient-Reported Quality of Life in Highest-Functioning Apert and Crouzon Syndromes

Crouzon and Apert syndromes are the most common syndromic forms of craniofacial dysostosis. Apert syndrome has a broad clinical spectrum, including complex craniofacial involvement, as well as limiting deformities of the hands, feet, and other joints that require multiple surgical procedures when compared with Crouzon syndrome, which is generally less severe. The authors hypothesized that the quality of life of Apert syndrome patients is inferior to that of Crouzon syndrome patients. The quality of life of Apert (n = 8) and Crouzon (n = 12) syndrome patients was assessed using the World Health Organization Quality of Life-100 questionnaire. The Mann-Whitney test was used to compare the quality-of-life scores between Apert and Crouzon patients. Values were considered significant for a confidence interval of 95 percent (p < 0.05). Apert patients showed an overall higher (score > 60 percent) quality of life in most World Health Organization Quality of Life-100 facets (68 percent) and domains (83.33 percent), with significance (p < 0.05) in three facets (energy and fatigue, mobility, and environment in the home), compared with Crouzon patients. Contrary to the authors' initial hypothesis, both the highest-functioning Apert patients and the Crouzon patients presented a satisfactory quality of life, demonstrating that these syndromic patients had acquired the necessary repertoire to manage the adverse daily situations of their lives.

Foramen Magnum Size and Involvement of Its Intraoccipital Synchondroses in Crouzon Syndrome

Cranial sutures and synchondroses tend to close prematurely in patients with Crouzon syndrome. This influences their skull vault and skull base development and may involve in common disturbances such as increased intracranial pressure and cerebellar tonsillar herniation. The authors' hypothesis was that Crouzon patients patients have a smaller foramen magnum than controls because of premature fusion of the intraoccipital synchondroses, putting them at risk for cerebellar tonsillar herniation. Therefore, foramen magnum size and time of intraoccipital synchondroses closure were evaluated and were related to the presence and degree of cerebellar tonsillar herniation. The foramen magnum surface area and anteroposterior diameter were measured on three-dimensional computed tomographic scans of 27 Crouzon patients and 27 age-matched controls. Scans had a slice-thickness between 0.75 and 1.25 mm and were aligned in a three-dimensional reformatting platform. The t test was used to study size differences. Synchondroses were graded as described by Madeline and Elster and studied with ordinal logistic regression analysis. Crouzon patients had a smaller foramen magnum surface area (602 mm versus 767 mm, p < 0.001) and anteroposterior diameter (31 mm versus 35 mm, p < 0.001) compared with controls. Differences stayed constant over time. Intraoccipital synchondroses closed 3 to 9 months earlier in Crouzon patients than in controls (p < 0.05). Since intraoccipital synchondroses close earlier in Crouzon patients, from early life on their foramen magnum is smaller compared with controls. Within Crouzon patients, the presence of cerebellar tonsillar herniation could not be related to foramen magnum size. Risk, II.

A Novel FGFR2 Mutation in Tyrosine Kinase II Domain, L617F, in Crouzon Syndrome

The purposes of this study were to find a novel mutation of FGFR2 in Korean Crouzon syndrome patients and to identify the functional consequences of this mutation. The samples consisted of 16 Crouzon patients. Peripheral venous blood was collected from the patients. FGFR2 mutation screening was performed by direct PCR sequencing of all exons and part of the introns. Restriction fragment length polymorphism (RFLP) analysis was performed to confirm the novel mutation. For functional studies, we performed luciferase assay for Runx2 transcriptional activity, real-time PCR for the bone markers (osteocalcin and alkaline phosphatase), and Western blot for phosphorylated FGFR2 and ERK1/2-MAPK protein. Among 16 patients, 10 showed FGFR2 mutations that had already been reported elsewhere. A novel FGFR2 mutation associated with tyrosine kinase II (TK-II) domain, L617F, was found in one Crouzon syndrome patient by direct PCR sequencing. Presence of this mutation was confirmed using RFLP analysis. Runx2 transcriptional activity and expression of osteocalcin and alkaline phosphatase significantly increased in L617F-transfected cells compared to wild-type cells. FGFR2 autophosphorylation in L617F-transfected cells increased in 1% serum, but ERK1/2-MAPK protein was not activated. The FGFR2-L617F mutation associated with the TK domain is potentially related to premature suture closure in Crouzon syndrome patient.

Prosthetic rehabilitation of a Crouzon patient: A case report

Crouzon syndrome is a rare genetic disorder, which can be defined as a variation of craniofacial dysostosis caused by the premature obliteration and ossification of two or more sutures. The growth pattern results in pseudoprognathism and malocclusions including an overcrowded or a widely spaced dentition. Specifically maxillary arch is narrow, high, and V-shaped. Cleft palate and bifid uvula are other possible features in the oral cavity. This report describes a non-surgical treatment model to overcome the remaining significant Class III intermaxillary relation and excessive tooth loss to recover function and aesthetics for a 25-year-old Crouzon patient.

頭蓋縫合早期癒合症に認めた気管形態異常

Tracheal cartilaginous sleeve (TCS) is a congenital malformation involving fusion of the tracheal arches that may be isolated to a few tracheal arches, include the entire trachea, or extend beyond the carina into the bronchi. Tracheotomy was required in 9 of 23 craniosynostosis cases undergoing gradual distraction at Osaka City General Hospital from March 2002 to April 2006. TCS was diagnosed in 5 of 9 cases-four Pfeiffer patients and one Crouzon patient. Diagnosis was made intraoperatively during tracheotomy or at autopsy. 3D-CT was not useful in diagnosing TCS. Aggressive management of respiratory infection and pulmonary secretion, selection of appropriate tracheostomy tubes, and endoscopic evaluation are very important to care in managing TCS patients.

Frontal Lobe Atrophy After Prolonged Frontal Bone Defect

After a frontofacial monobloc in a 12-year-old Crouzon patient, the frontal bone was lost to infection. The patient did not attend postoperative appointments and was lost to follow-up. Nine years later, he reappeared requesting surgical reconstruction. This was performed satisfactorily with a titanium plate; however, it became apparent later that he had considerable atrophy of the frontal lobes and had developed the unstable behavior of patients who have undergone a frontal lobotomy. The atrophy would appear to be the consequence of the long-term absence of the frontal bones and the resultant repetitive frontal lobe microtrauma. Frontal infection and subsequent loss of the frontal bone is a recognized complication of monobloc advancement for faciocraniosynostosis and is mainly caused by the communication between the oronasal cavities and the cranial base. The frontal bone defect would normally be repaired after a delay of 6 months to a year with no significant sequelae. We present the unusual case of a patient whose frontal defect was not reconstructed for 9 years and who, as a result, developed frontal lobe atrophy and subsequent severe psychologic and behavioral difficulties.

Ｃｒｏｕｚｏｎ ｓｙｎｄｒｏｍｅにおける顔貌の連続的形質変異の定量的解析

The purpose of this study was 1) to obtain polygon data and individual parameters from facial photographs of Crouzon syndrome patients and general patients with malocclusion in order to synthesize facial images using a 3 D wire frame model, and 2) to distinguish between Crouzon syndrome patients and general patients with malocclusion using quantitative analysis of characteristic variations of facial features. The face images were prepared from standardized full-face photographs of 10 Crouzon patients (Crouzon group) and 10 general patients with malocclusion (General group). These facial images were fitted to the 3 D wire frame model and the polygon data were obtained. Following application of principal component analysis, the individual parameters of the standard face were considered to be individual feature parameters. Linear discriminant analysis using the individual feature parameters was applied to distinguish both groups, and the validity of this statistical method was estimated. Moreover, the discriminant rates of the parts of the face were calculated and compared to those of the full face. A discriminant rate of 90% was obtained. The application of individual feature parameters to facial features could be used to objectively distinguish between these two groups. The discriminant rates of the part of the face were lower than those of the full face. This method seemed to be effective for diagnosing congenital anomalies from facial features. Further research on other congenital anomalies would be necessary to apply this analysis as a new diagnostic step.

Mutation analysis of Crouzon syndrome in Taiwanese patients

Crouzon syndrome is an autosomal-dominant disorder that causes premature fusion of the cranial suture. Crouzon, Pfeiffer, and Apert syndromes are caused by mutations in the extracellular, third immunoglobulin-like domain, and adjacent linker regions (exons IIIa and IIIc) of the fibroblast growth factor receptor 2 (FGFR2) gene. We screened 12 Crouzon syndrome patients for mutations in exons IIIa and IIIc of the FGFR2 gene by polymerase chain reaction (PCR) and direct sequencing. Mutations were detected in nine of 12 patients at amino acid positions 278, 281, 289, 342, and 354. More than half of the studied Crouzon patients carried a mutation resulting in either the loss or gain of a cysteine residue. A novel missense Ser354Phe substitution at exon IIIc of the human FGFR2 gene was found. According to our results, sequencing analysis of IgIII domain of the FGFR2 gene can lead to a genetic diagnosis of Crouzon syndrome.

Chiari malformation and odontoid panus causing craniovertebral stenosis in a child with Crouzon’s syndrome

Crouzon's disease is a well-known disorder affecting multiple organ systems, specifically a craniofacial disorder with highly variable penetrance and severity of deformity. Crouzon's patients typically have anomalies of the skull base leading to gross distortion of the cranium and in some cases the cervicocranium. We present a 5-year-old girl with Crouzon's disease who suffered from an acquired Chiari I malformation after insertion of a ventriculoperitoneal shunt and a coexistent ventral odontoid panus. Both these lesions were causing cervicomedullary compression. The literature is controversial on the surgical management of anterior and posterior compression at the craniocervical junction. We review the literature on surgical options for decompression at the craniocervical junction and offer our surgical case as a treatment option for patients in this rare clinical situation.

FGFR2 mutations among Thai children with Crouzon and Apert syndromes.

Crouzon and Apert syndromes have been reported to be associated with mutations in Fibroblast Growth Factor Receptor 2 (FGFR2) gene in various ethnic groups, but never in Southeast Asian subjects. Therefore, the authors conducted a study to characterize 11 Thai patients: four with Crouzon syndrome and seven with Apert syndrome. All cases are sporadic. Mean paternal and maternal ages were 38.7 and 28.6 years, respectively. Molecularly, all patients were found to have mutations in the FGFR2 gene. Three mutations (C278F, S347C, S351C) were detected in all Crouzon patients with two having S351C. The seven patients with Apert syndrome have either S252W or P253R mutation. The authors' findings that sporadic cases were associated with advanced paternal age and that they all had mutations in FGFR2 are consistent with previous reports. This is another observation supporting the causative role of FGFR2 mutations in Crouzon and Apert syndromes.

Crouzon's syndrome: differential in vitro secretion of bFGF, TGFbeta I isoforms and extracellular matrix macromolecules in patients with FGFR2 gene mutation.

In the Crouzon's syndrome the cranial morphogenic processes are altered due to the early fusion of cranial sutures. We analysed the phenotype of cultured fibroblasts from normal subjects and from Crouzon patients with a specific fibroblast growth factor receptor 2 mutation resulting in a Cys 342 Tyr substitution within the third immunoglobulin domain. Crouzon fibroblasts differed from normal fibroblasts in their extracellular matrix macromolecule accumulation. In Crouzon fibroblasts glycosaminoglycans and fibronectin were decreased and type I collagen increased. As transforming growth factors beta (TGF beta) and basic fibroblasts growth factor (bFGF) together regulate extracellular matrix deposition, we evaluated TGF beta(1), TGF beta(3) and bFGF production by Crouzon and normal fibroblasts. TGF beta(1), TGFb(3) and bFGF levels were lower while TGF beta(1) mRNA transcripts were higher in Crouzon cells. As the increased TGF beta(1) gene expression did not translate into a parallel increase of secreted TGF beta(1), control of TGF beta(1) secretion may be mainly post-transcriptional. Furthermore, adding bFGF increased TGF beta(1) and TGF beta(3) secretion, suggesting the drop may be due to the altered signal transduction of bFGF. These innovative data suggest the in vitro differences between normal and Crouzon fibroblasts may be due to an imbalance in TGF beta and bFGF levels which alters the microenvironment where morphogenesis takes place.

Sequence analysis of fibroblast growth factor receptor 2 ( FGFR2 ) in Japanese patients with craniosynostosis.

Recently, mutations of the fibroblast growth factor receptor ( FGFR ) genes have been detected in syndromic craniosynostosis. We examined nucleotide sequences of FGFR2 in Japanese craniosynostosis patients (Crouzon syndrome: 9 cases; Apert syndrome: 6 cases; scaphocephaly: 3 cases as non-syndromic patients) by polymerase chain reaction (PCR) followed by direct sequencing methods. The results demonstrated FGFR2 heterozygous mutations at codons 252, 290 of exon 7, and at codon 342, 354 of exon 9 in Crouzon syndromes. In Apert syndrome patients, Ser252Trp and Pro253Arg were detected in five and one patients, respectively. No mutation was detected in one case of Crouzon, all cases of scaphocephaly and healthy individuals. Thus far sequence analysis of FGFR2 in syndromic craniosynostosis has been reported in many white patients, whereas in Japanese only several cases have been studied. The current study with 18 patients confirmed that a similar series of mutations occur in Japanese patients as in white patients regardless of ethnicity and environment. The frequency of the mutation was 82% (9/11 cases) in Japanese Crouzon patients. The ratio of S252W:P253R was 5 : 1 in Japanese Apert patients. Moreover, in Japanese Apert patients, complication rate of cleft palate was 60% for mutation of Ser252Trp and 0 of 2 patients for Pro253Arg, with their syndactyly score being 4.90 and 5.50, respectively.

Mutation analysis of Crouzon syndrome and identification of one novel mutation in Taiwanese patients.

Crouzon syndrome is an autosomal dominant disorder causing premature fusion of the cranial suture. Mutations have been reported in exon IIIa or IIIc of the fibroblast growth factor receptor 2 (FGFR2) gene. In the present study, nine unrelated Crouzon syndrome patients were screened for mutations in the two exons of FGFR2 by polymerase chain reaction and direct sequencing. Mutations were detected in 67% (6/9) of all cases. More than half the studied Crouzon patients carried a mutation resulting in either the loss or gain of a cysteine residue. A novel mutation, Tyr281Cys substitution, was discovered at exon IIIa. The mechanisms by which the same genotypes cause different phenotypes for each type of craniosynostosis syndrome in still uncertain. However, the molecular identification of the FGFR gene has made a great impact on the clinical classification of craniosynostosis syndromes; a new classification based on genotypes seems to be unavoidable.

Role of the extracellular matrix and growth factors in skull morphogenesis and in the pathogenesis of craniosynostosis.

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.

Description of a new mutation and characterization ofFGFR1, FGFR2, andFGFR3 mutations among Brazilian patients with syndromic craniosynostoses

Dominant mutations in three fibroblast growth factor receptor genes (FGFRs1-3) cause Crouzon, Jackson-Weiss, Pfeiffer, and Apert syndromes. In the present study, 50 Brazilian patients with these four syndromes (27 Apert, 17 Crouzon, 5 Pfeiffer, and 1 Jackson-Weiss patients) were screened for mutations in the FGFR1-3 genes. Except for one, all the Apert patients had either S252W (n = 16) or P253R (n = 10) mutations. The remaining Apert case is atypical with a mutation altering the splice site of FGFR2 exon IIIc. The Pfeiffer patients had mutations in one of the FGFR genes: three in FGFR2, one in FGFR1, and one in FGFR3. In contrast, only 8 of the 17 Crouzon patients studied had a mutation in either FGFR2 (n = 7) or FGFR3 locus (n = 1). Mutations in the FGFR2 locus account for most (93%) of our syndromic craniosynostotic cases, whereas 5% had mutations in the FGFR3 locus and only 2% had mutations in the FGFR1 gene. Except for one, all the other mutations were reported previously in craniosynostotic patients from other populations. Interestingly, the mutation C278F, previously described in Crouzon and Pfeiffer cases, was here identified in a familial case with Jackson-Weiss. Also, unexpectedly, a common mutation altering the splice site of the FGFR2 exon IIIc was found in one Apert and two Pfeiffer patients. In addition, we identified a new mutation (A337P) in the FGFR2 exon IIIc associated with Crouzon phenotype.