ABSTRACT
BACKGROUND: Crouzon syndrome ([OMIM] #123500) caused by FGFR2 mutation is an autosomal dominant syndrome with craniosynostosis, the underlying mechanism of which remains obscure. METHODS: First, whole exome sequencing was used to screen the possible pathogenic variant in two sporadic patients with Crouzon syndrome. The investigation of primary and secondary structures as well as the conservation analysis of FGFR2 mutation (p.Cys342Arg) was performed. Then, wild-type and mutant overexpression plasmids were constructed and transfected into pre-osteoblastic murine cell line MC3T3-E1 cells. Osteogenesis and mitochondrial metabolism were analyzed by CCK8, ALP staining and ALP activity, alizarin red staining, qRT-PCR, Western blot, seahorse assays and mitochondrial staining. The siRNA targeting FGFR2 and domain negative FGFR2 were designed for verification. RESULTS: First, FGFR2 mutation (p.Cys342Arg) was detected in two sporadic Chinese Crouzon syndrome patients. FGFR2 p.Cys342Arg promoted the osteogenic differentiation of MC3T3-E1 cells through the upregulation of AMP-activated protein kinase (AMPK)-Erk1/2 signal pathway. Furthermore, FGFR2 p.Cys342Arg enhanced oxidative phosphorylation and converted mitochondrial fusion to the fission of MC3T3-E1, promoting osteogenic differentiation and craniosynostosis in Crouzon syndrome. Additionally, AMPK or Erk1/2 inhibitors delayed the cranial suture closure. CONCLUSION: FGFR2 mutation p.Cys342Arg promotes osteogenesis by enhancing mitochondrial metabolism-mediated via FGF/FGFR-AMPK-Erk1/2 axis, which indicates the potential of therapy targeting AMPK or Erk1/2 for syndromic craniosynostosis treatment.
Subject(s)
Craniofacial Dysostosis , Craniosynostoses , AMP-Activated Protein Kinases/genetics , Animals , Craniofacial Dysostosis/genetics , Craniofacial Dysostosis/pathology , Craniosynostoses/genetics , Fibroblast Growth Factor 2/genetics , Humans , Mice , Mitogen-Activated Protein Kinase 3/metabolism , Mutation/genetics , Osteogenesis/genetics , RNA, Small Interfering , Receptor, Fibroblast Growth Factor, Type 2/geneticsABSTRACT
The cranial endo and dermal skeletons, which comprise the vertebrate skull, evolved independently over 470 million years ago and form separately during embryogenesis. In mammals, much of the cartilaginous chondrocranium is transient, undergoing endochondral ossification or disappearing, so its role in skull morphogenesis is not well studied and it remains an enigmatic structure. We provide complete 3D reconstructions of the laboratory mouse chondrocranium from embryonic day (E) 13.5 through E17.5 using a novel methodology of uncertainty-guided segmentation of phosphotungstic enhanced 3D micro-computed tomography images with sparse annotation. We evaluate the embryonic mouse chondrocranium and dermatocranium in 3D, and delineate the effects of a Fgfr2 variant on embryonic chondrocranial cartilages and on their association with forming dermal bones using the Fgfr2cC342Y/+ Crouzon syndrome mouse. We show that the dermatocranium develops outside of and in shapes that conform to the chondrocranium. Results reveal direct effects of the Fgfr2 variant on embryonic cartilage, on chondrocranium morphology, and on the association between chondrocranium and dermatocranium development. Histologically, we observe a trend of relatively more chondrocytes, larger chondrocytes, and/or more matrix in the Fgfr2cC342Y/+ embryos at all timepoints before the chondrocranium begins to disintegrate at E16.5. The chondrocrania and forming dermatocrania of Fgfr2cC342Y/+ embryos are relatively large, but a contrasting trend begins at E16.5 and continues into early postnatal (P0 and P2) timepoints, with the skulls of older Fgfr2cC342Y/+ mice reduced in most dimensions compared to Fgfr2c+/+ littermates. Our findings have implications for the study and treatment of human craniofacial disease, for understanding the impact of chondrocranial morphology on skull growth, and potentially on the evolution of skull morphology.
Subject(s)
Craniofacial Dysostosis , Receptor, Fibroblast Growth Factor, Type 2 , Animals , Cartilage , Craniofacial Dysostosis/pathology , Disease Models, Animal , Mammals , Mice , Receptor, Fibroblast Growth Factor, Type 2/genetics , Skull/anatomy & histology , X-Ray MicrotomographyABSTRACT
BACKGROUND: In this study, the authors present the outcomes of 4 patients with a severe form of Crouzon syndrome characterized by mutation of fibroblast growth factor receptor 2 (FGFR2) c.1040 C > G p.Ser347Cys or the pathogenic c.1061C > G p.Ser354Cys variant of FGFR2, who underwent posterior vault distraction osteogenesis (PVDO) to alleviate elevated intracranial pressure. METHODS: Patients with diagnosed Crouzon syndrome who were found by genetic testing to have an FGFR2 c.1040 C > G p.Ser347Cys mutation or the c.1061C > G p.Ser354Cys variant were included. Outcome data and presence of hydrocephalus, Chiari Malformation type I (CMIs), and the presence/absence of a tracheostomy were recorded. RESULTS: Three patients with the FGFR2 c.1040 C > G p.Ser347Cys mutation and 1 with the pathogenic FGFR2 c.1061C > G p.Ser354Cys variant were identified as having characteristics of severe Crouzon syndrome. The mean age at PVDO was 15 months and the mean posterior advancement was 20 mm. All 4 patients experienced sufficient relief of the elevated intracranial pressure from the PVDO to prevent the need for shunt placement, stabilize the ventricular dimensions (n = 2), and resolve the CMIs (n = 2). Intracranial pressure screening ruled out malignant cerebrospinal fluid volume increase. CONCLUSIONS: PVDO effectively prevented hydrocephalus and resolved CMIs, successfully alleviating intracranial pressure and maximizing clinical outcomes for patients with severe Crouzon syndrome.
Subject(s)
Craniofacial Dysostosis , Craniosynostoses , Hydrocephalus , Intracranial Hypertension , Osteogenesis, Distraction , Craniofacial Dysostosis/genetics , Craniofacial Dysostosis/pathology , Craniofacial Dysostosis/surgery , Craniosynostoses/diagnosis , Humans , Hydrocephalus/genetics , Hydrocephalus/surgery , Mutation , Osteogenesis, Distraction/methods , Receptor, Fibroblast Growth Factor, Type 2/geneticsABSTRACT
Nager syndrome epitomizes the acrofacial dysostoses, which are characterized by craniofacial and limb defects. The craniofacial defects include midfacial retrusion, downslanting palpebral fissures, prominent nasal bridge, and micrognathia. Limb malformations typically include hypoplasia or aplasia of radial elements including the thumb. Nager syndrome is caused by haploinsufficiency of SF3B4, encoding a spliceosomal protein called SAP49. Here, we report a patient with a loss of function variant in SF3B4 without acrofacial dysostosis or limb defects, whose reason for referral was developmental and growth delay. This patient is evidence of a broader phenotypic spectrum associated with SF3B4 variants than previously appreciated.
Subject(s)
Genetic Predisposition to Disease , Mandibulofacial Dysostosis/genetics , RNA Splicing Factors/genetics , Spliceosomes/genetics , Craniofacial Dysostosis/genetics , Craniofacial Dysostosis/pathology , Haploinsufficiency/genetics , Humans , Infant , Limb Deformities, Congenital/genetics , Limb Deformities, Congenital/pathology , Male , Mandibulofacial Dysostosis/pathology , Mutation/genetics , Phenotype , Spliceosomes/pathologyABSTRACT
RATIONALE: Crouzon syndrome is a craniofacial malformation caused by premature fusion of fibrous sutures in infants. It is one of the most common craniosynostosis syndromes, and surgery is the only effective treatment for correcting it. Postoperative complications such as encephalocele, infections, hematoma have been reported. We herein report a case of a 62-month-old boy with Crouzon syndrome who underwent fronto-orbital advancing osteotomy, cranial vault remolding, and extensive osteotomy and subsequently developed left proptosis and severe chemosis, these complications are rare and we believe it will be of use to clinicians, physicians, and researchers alike. PATIENT CONCERNS: The patient's skull had been malformed since birth, and he had been experiencing paroxysmal headaches coupled with vomiting for 4 months. Having never received prior treatment, he underwent fronto-orbital advancement at our clinic; afterward, left proptosis and severe chemosis occurred. DIAGNOSIS: The patient was diagnosed with Crouzon syndrome, and the complications included left proptosis and severe chemosis, confirmed by the clinical manifestations, physical examination, and computed tomography (CT). INTERVENTION: We carried out cranial vault remodeling and fronto-orbital advancement. We applied ophthalmic chlortetracycline ointment on the conjunctivae, elevated the patient's head, evacuated the hematoma, and carried out a left blepharorrhaphy. OUTCOMES: The proptosis and chemosis resolved with no recurrence. No other complications occurred during the follow-up period (12âmonths), and CT scans revealed that the hematoma had disappeared. The calvarial vault reshaping was satisfactorily performed, and the patient's vision was not impaired. LESSONS: Severe proptosis and chemosis are rare complications that can occur after fronto-orbital advancement for Crouzon syndrome. A detailed preoperative examination (including magnetic resonance imaging and CT) is essential for diagnosis. Complete hemostasis, evacuation of hematoma, and placement of a periorbital drainage tube during surgery all contribute to an effective treatment plan. An ophthalmic ointment should be administered, and the patient's head should be elevated during the procedure. Evacuation of retrobulbar epidural hematoma and blepharorrhaphy could also help relieve proptosis and chemosis. Our report describes 2 rare complications associated with the treatment for Crouzon syndrome, and we believe it will be of use to clinicians, physicians, and researchers alike.
Subject(s)
Craniofacial Dysostosis/surgery , Exophthalmos/etiology , Frontal Bone/surgery , Ophthalmologic Surgical Procedures/adverse effects , Orbit/surgery , Plastic Surgery Procedures/adverse effects , Child, Preschool , Craniofacial Dysostosis/diagnosis , Craniofacial Dysostosis/pathology , Eyelid Diseases/pathology , Eyelid Diseases/surgery , Frontal Bone/abnormalities , Humans , Male , Ophthalmologic Surgical Procedures/methods , Orbit/abnormalities , Osteotomy/methods , Plastic Surgery Procedures/methods , Retrobulbar Hemorrhage/diagnostic imaging , Retrobulbar Hemorrhage/surgery , Skull/surgery , Tomography, X-Ray Computed/methods , Treatment Outcome , Vision Disorders/surgeryABSTRACT
BACKGROUND: Considerable craniofacial features of Crouzon syndrome are attributed to the dysmorphology of the cranial base. As cephalometric studies have focused mainly on the facial deformity, rather than the cranial base, the underlying cause of deformity is not as well understood. Therefore, the authors compared the cranial base development of Crouzon syndrome to controls to trace the timing of deformity in the cranial base and face, to analyze their temporal correlation. METHODS: Ninety computed tomographic scans were included (Crouzon, n = 36; controls, n = 54) and divided into five age subgroups. Craniofacial cephalometric measurements were analyzed by Materialise software. RESULTS: The overall cranial base length in Crouzon syndrome compared with controls decreased 8 percent (p = 0.014) on average. The posterior cranial fossa shortening accounted for most of this reduction. The cranial base displaced with the distances from basion, sella, and ethmosphenoid to posterior nasal spine shortened by 21%, 18%, and 16%, respectively (all p < 0.01) during life. Although the cranial base angle on intracranial surface remains normal, the angles on facial surface narrowed were reduced. CONCLUSIONS: The cranial base deformity of Crouzon syndrome consists of the whole skull base and particularly anterior skull base shortening early, leading to a compensatory widened anterior skull base. However, when this widening did not compensate fully for the rapid enlargement of the brain, the posterior skull base displaced inferiorly and became kyphotic. The cranial base deformity develops sequentially anterior to posterior in a probable cascade of influence pattern. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, II.
Subject(s)
Craniofacial Dysostosis/pathology , Skull Base/abnormalities , Adolescent , Adult , Age Factors , Case-Control Studies , Child , Child, Preschool , Craniofacial Dysostosis/diagnostic imaging , Face/abnormalities , Facial Asymmetry/diagnostic imaging , Facial Asymmetry/pathology , Female , Humans , Infant , Infant, Newborn , Longitudinal Studies , Male , Middle Aged , Skull Base/diagnostic imaging , Tomography, X-Ray Computed , Young AdultSubject(s)
Craniofacial Abnormalities/diagnostic imaging , Face/diagnostic imaging , Imaging, Three-Dimensional/instrumentation , Printing, Three-Dimensional/instrumentation , Cleft Lip/diagnostic imaging , Cleft Lip/pathology , Craniofacial Abnormalities/pathology , Craniofacial Dysostosis/diagnostic imaging , Craniofacial Dysostosis/pathology , Face/abnormalities , Female , Fetus/abnormalities , Fetus/diagnostic imaging , Gestational Age , Humans , Pregnancy , Preoperative Period , Ultrasonography, Prenatal/methods , Ultrasonography, Prenatal/standardsABSTRACT
FGFR2c regulates many aspects of craniofacial and skeletal development. Mutations in the FGFR2 gene are causative of multiple forms of syndromic craniosynostosis, including Crouzon syndrome. Paradoxically, mouse studies have shown that the activation (Fgfr2cC342Y; a mouse model for human Crouzon syndrome), as well as the removal (Fgfr2cnull), of the FGFR2c isoform can drive suture abolishment. This study aims to address the downstream effects of pathogenic FGFR2c signalling by studying the effects of Fgfr2c overexpression. Conditional overexpression of Fgfr2c (R26RFgfr2c;ßact) results in craniofacial hypoplasia as well as microtia and cleft palate. Contrary to Fgfr2cnull and Fgfr2cC342Y, Fgfr2c overexpression is insufficient to drive onset of craniosynostosis. Examination of the MAPK/ERK pathway in the embryonic sutures of Fgfr2cC342Y and R26RFgfr2c;ßact mice reveals that both mutants have increased pERK expression. The contrasting phenotypes between Fgfr2cC342Y and R26RFgfr2c;ßact mice prompted us to assess the impact of the Fgfr2c overexpression allele on the Crouzon mouse (Fgfr2cC342Y), in particular its effects on the coronal suture. Our results demonstrate that Fgfr2c overexpression is sufficient to partially rescue craniosynostosis through increased proliferation and reduced osteogenic activity in E18.5 Fgfr2cC342Y embryos. This study demonstrates the intricate balance of FGF signalling required for correct calvarial bone and suture morphogenesis, and that increasing the expression of the wild-type FGFR2c isoform could be a way to prevent or delay craniosynostosis progression.
Subject(s)
Bone and Bones/abnormalities , Bone and Bones/pathology , Craniofacial Dysostosis/pathology , Craniosynostoses/pathology , Receptor, Fibroblast Growth Factor, Type 2/metabolism , Alkaline Phosphatase/metabolism , Alleles , Animals , Cell Proliferation , Cleft Palate/pathology , Congenital Microtia/genetics , Congenital Microtia/pathology , Cranial Sutures/pathology , Craniofacial Dysostosis/genetics , Craniosynostoses/genetics , HEK293 Cells , Humans , MAP Kinase Signaling System , Mice , Mutation/genetics , Neural Crest/metabolism , Neural Crest/pathology , Phenotype , Receptor, Fibroblast Growth Factor, Type 2/genetics , Skull/pathologyABSTRACT
Midface dysgenesis is a feature of more than 200 genetic conditions in which upper airway anomalies frequently cause respiratory distress, but its etiology is poorly understood. Mouse models of Apert and Crouzon craniosynostosis syndromes exhibit midface dysgenesis similar to the human conditions. They carry activating mutations of Fgfr2, which is expressed in multiple craniofacial tissues during development. Magnetic resonance microscopy of three mouse models of Apert and Crouzon syndromes revealed decreased nasal passage volume in all models at birth. Histological analysis suggested overgrowth of the nasal cartilage in the two Apert syndrome mouse models. We used tissue-specific gene expression and transcriptome analysis to further dissect the structural, cellular and molecular alterations underlying midface and upper airway dysgenesis in Apert Fgfr2+/S252W mutants. Cartilage thickened progressively during embryogenesis because of increased chondrocyte proliferation in the presence of Fgf2 Oral epithelium expression of mutant Fgfr2, which resulted in a distinctive nasal septal fusion defect, and premature facial suture fusion contributed to the overall dysmorphology. Midface dysgenesis in Fgfr2-related craniosynostosis is a complex phenotype arising from the combined effects of aberrant signaling in multiple craniofacial tissues.
Subject(s)
Cell Cycle , Craniosynostoses/embryology , Face/abnormalities , Organ Specificity , Receptor, Fibroblast Growth Factor, Type 2/metabolism , Respiratory System Abnormalities/embryology , Respiratory System Abnormalities/pathology , Acrocephalosyndactylia/pathology , Animals , Cartilage/pathology , Cell Proliferation , Chondrocytes/pathology , Cranial Sutures/pathology , Craniofacial Dysostosis/embryology , Craniofacial Dysostosis/pathology , Craniosynostoses/pathology , Disease Models, Animal , Embryo, Mammalian/abnormalities , Embryo, Mammalian/pathology , Face/embryology , Face/pathology , Gene Expression Regulation, Developmental , Mice, Inbred C57BL , Mice, Mutant Strains , Nose/abnormalities , Nose/embryology , Nose/pathology , Receptor, Fibroblast Growth Factor, Type 2/geneticsABSTRACT
Activating mutations of fibroblast growth factor receptors (FGFRs) are a major cause of skeletal dysplasias, and thus they are potential targets for pharmaceutical intervention. BMN 111, a C-type natriuretic peptide analog, inhibits FGFR signaling at the level of the RAF1 kinase through natriuretic peptide receptor 2 (NPR2) and has been shown to lengthen the long bones and improve skull morphology in the Fgfr3Y367C/+ thanatophoric dysplasia mouse model. Here we report the effects of BMN 111 in treating craniosynostosis and aberrant skull morphology in the Fgfr2cC342Y/+ Crouzon syndrome mouse model. We first demonstrated that NPR2 is expressed in the murine coronal suture and spheno-occipital synchondrosis in the newborn period. We then gave Fgfr2cC342Y/+ and Fgfr2c+/+ (WT) mice once-daily injections of either vehicle or reported therapeutic levels of BMN 111 between post-natal days 3 and 31. Changes in skeletal morphology, including suture patency, skull dimensions, and long bone length, were assessed by micro-computed tomography. Although BMN 111 treatment significantly increased long bone growth in both WT and mutant mice, skull dimensions and suture patency generally were not significantly affected. A small but significant increase in the relative length of the anterior cranial base was observed. Our results indicate that the differential effects of BMN 111 in treating various skeletal dysplasias may depend on the process of bone formation targeted (endochondral or intramembranous), the specific FGFR mutated, and/or the specific signaling pathway changes due to a given mutation.
Subject(s)
Craniofacial Dysostosis/drug therapy , Craniosynostoses/drug therapy , Natriuretic Peptide, C-Type/analogs & derivatives , Animals , Animals, Newborn , Craniofacial Dysostosis/genetics , Craniofacial Dysostosis/pathology , Craniosynostoses/genetics , Disease Models, Animal , Female , Male , Mice , Mice, Transgenic , Natriuretic Peptide, C-Type/therapeutic use , Receptor, Fibroblast Growth Factor, Type 2/genetics , Treatment OutcomeABSTRACT
BACKGROUND: FGFR2 encodes a fibroblast growth factor receptor whose mutations are responsible for the Crouzon syndrome, involving craniosynostosis and facial dysostosis with shallow orbits. However, few reports are available quantifying the orbital volume of Crouzon syndrome and there was little direct evidence to show FGFR2 mutation actually influencing orbital morphology. METHODS: Ten Crouzon syndrome patients underwent a standard ophthalmologic assessment. Morphology study was carried out based on 3-dimensional computed tomography scan to calculate orbital volume. Genomic DNA was extracted from peripheral blood leukocytes of the patients and genomic screening of FGFR2. A three-dimensional computer model was used to analyse the structural positioning of the mutation site that was predicted possible impact on functional of FGFR2 protein. Real-time PCR was performed to analyse the expression of bone maker gene. RESULTS: We describe a FGFR2 mutation (p.G338R, c.1012G > C) in a Chinese family with Crouzon syndrome. Computational analysis showed the mutate protein obviously changes in the local spatial structure compared with wild-type FGFR2. The expression of osteocalcin and alkaline phosphatase two osteoblast specific genes significantly increased in orbital bone directly from patient compared to normal individual, which may lead to facial dysostosis. This is compatible with the shallow and round orbits in our Crouzon syndrome patient. CONCLUSIONS: Our study further identified G338R FGFR2 mutation (c1012G > C) lead to inherited Crouzon syndrome. Thus, early intervention, both medically and surgically, as well as disciplined by a multiple interdisciplinary teams are crucial to the management of this disorder.
Subject(s)
Alkaline Phosphatase/genetics , Craniofacial Dysostosis/genetics , Craniofacial Dysostosis/pathology , Genetic Predisposition to Disease , Mutation , Osteocalcin/genetics , Receptor, Fibroblast Growth Factor, Type 2/genetics , Adolescent , Amino Acid Sequence , Case-Control Studies , Female , Follow-Up Studies , Humans , Infant , Male , Middle Aged , Osteogenesis , Pedigree , Prognosis , Protein Conformation , Sequence HomologyABSTRACT
INTRODUCTION: The morphology of the skull base can be altered in craniosynostoses. The objective of this study is to evaluate the reduced intercarotid artery distance in the lacerum segment in patients with syndromic and isolated brachycephaly. MATERIALS AND METHODS: The distances between the inner walls of the carotid canal at the lacerum segment were measured on high-resolution CT scans in children with Crouzon (25), Pfeiffer (21), Apert (26), Saethre-Chotzen (7) syndromes, isolated bicoronal synostosis (9), and compared to an age-matched control group (30). RESULTS: A significantly smaller mean distance between carotid canal walls was observed in Crouzon (11.1 ± 4.9 mm), Pfeiffer (9.6 ± 5.1 mm), Apert (12.3 ± 4.3 mm), Saethre-Chotzen (14.8 ± 3.0 mm) syndromes, and isolated bicoronal synostosis (14.9 ± 3.7 mm) as compared to the control group (19.7 ± 2.4 mm, P < 0.001, P < 0.001, P < 0.001, P = 0.005, and P = 0.002, respectively). There was no statistically significant difference in intercarotid canal distance among the Apert, Saethre-Chotzen and isolated bicoronal synostosis groups. Overall, the brachycephalic group showed reduced intercarotid canal distance comparing to controls (P < 0.001). DISCUSSION AND CONCLUSIONS: There is significant reduction of the distance between carotid canals in brachycephalic patients. This distance is more significantly altered in FGFR-related brachycephaly syndromes (especially Crouzon and Pfeiffer syndromes), than Saethre-Chotzen syndrome (TWIST1 mutation) and isolated non-syndromic bicoronal synostosis. This study highlights the importance of FGFRs in shaping the skull base. Altered vascular course of the internal carotid arteries can have important implications in planning skull base surgery in brachycephalic patients.
Subject(s)
Carotid Arteries/pathology , Craniosynostoses/pathology , Adolescent , Carotid Arteries/diagnostic imaging , Carotid Arteries/growth & development , Case-Control Studies , Child , Child, Preschool , Craniofacial Dysostosis/diagnostic imaging , Craniofacial Dysostosis/pathology , Craniofacial Dysostosis/surgery , Craniosynostoses/diagnostic imaging , Craniosynostoses/surgery , Female , Humans , Infant , Male , Organ Size , Plastic Surgery Procedures , Retrospective Studies , Skull Base/diagnostic imaging , Skull Base/growth & development , Skull Base/pathology , Tomography, X-Ray Computed , Young AdultABSTRACT
OBJECTIVES: Fibroblast growth factor receptor 2 (FGFR2) C342Y/+ mutation is a known cause of Crouzon syndrome that is characterised by craniosynostosis and midfacial hypoplasia. Our aim was to conduct extensive phenotyping of the maxillary, mandibular and dental morphology associated with this mutation. MATERIALS AND METHODS: Morphometric data were obtained from 40 mice, representing two genotypes (Crouzon and wild-type) and two sexes (males and females) (n=10 in each group). Dental analysis further categorised the first molars into the two jaws (maxillary and mandibular) (n=20 in each group). Maxillary, mandibular and dental morphology was compared by analysing 23 linear landmark-based dimensions in three-dimensional micro-computed tomography reconstructions. RESULTS: Compared with wild-type, Crouzon (FGFR2C342Y/+) maxillae were significantly shorter in maximum height, anterior and posterior lengths and middle width, but larger in posterior width (p<0.05 for height; p<0.001 for other comparisons). In the Crouzon mandible, the ascending and descending heights, effective and mandibular lengths, and intercoronoid and intercondylar widths were significantly shorter, whereas intergonial width was larger (p<0.01 for intercondylar width; p<0.001 for other comparisons). Crouzon teeth were significantly smaller mesiodistally, but larger in crown height (p<0.001 for each comparison). All Crouzon mice presented with bifid mandibular condyles and a quarter presented with expansive bone lesions in the mandibular incisor alveolus. CONCLUSIONS: Our findings of hypoplasia in all three planes in Crouzon maxillae and mandibles, together with the presence of bifid mandibular condyles and expansive bone lesions, may be relevant to maxillofacial surgery and orthodontics. Beyond skeletal effects, the FGFR2C342Y/+ mutation is now implicated in affecting tooth development. This study's skeletal phenomics data also provides baseline data against which the effect of various treatments can now be assessed.
Subject(s)
Craniofacial Dysostosis/pathology , Mandible/pathology , Maxilla/pathology , Animals , Craniofacial Dysostosis/diagnostic imaging , Disease Models, Animal , Female , Genotype , Imaging, Three-Dimensional , Male , Mandible/diagnostic imaging , Maxilla/diagnostic imaging , Mice , Phenotype , X-Ray MicrotomographyABSTRACT
The aim of the present study was to identify mutations in the fibroblast growth factor receptor 2 (FGFR2) gene in patients with Crouzon syndrome and characterize the associated clinical features. A total of two Chinese patients diagnosed with Crouzon syndrome underwent complete examinations, including bestcorrected visual acuity, slitlamp, examination, fundus examination, optical coherence tomography and computed tomography of the skull. Genomic DNA was extracted from peripheral blood samples collected from the patients, as well as their family members and 200 unrelated control subjects from the same population. Exons 8 and 10 in the FGFR2 gene were amplified by polymerase chain reaction and directly sequenced. Patient #1 had a heterozygous missense mutation (c.1025G>A, p.C342Y) in exon 10 of FGFR2. Patient #2 had a heterozygous mutation (c.1084+1 G>T; IVS10+1G>T) in intron 10. The mutations were not present in any of the unaffected family members or unrelated control subjects. These findings expand the mutation spectrum of FGFR2, and are valuable for genetic counseling in addition to prenatal diagnosis in patients with Crouzon syndrome.
Subject(s)
Craniofacial Dysostosis/genetics , Genetic Predisposition to Disease , Receptor, Fibroblast Growth Factor, Type 2/genetics , Adult , Asian People , Child, Preschool , Craniofacial Dysostosis/pathology , Exons/genetics , Female , Heterozygote , Humans , Mutation/genetics , PedigreeABSTRACT
INTRODUCTION: Sinus pericranii is a rare vascular malformation that connects the intracranial dural sinuses to the extracranial venous drainage system and is caused by either trauma or congenital defects. Although the majority of these vascular structures are due to trauma, some are congenital. CASE REPORT: Herein, we report a 5-month-old patient with a very large and fluctuating subcutaneous mass over the occiput and the diagnosis of Crouzon's syndrome. The child presented with a large midline mass that on imaging, connected to the underlying torcular and was diagnosed as a sinus pericranii. At long-term follow-up and without operative intervention, the sinus pericranii resolved. This uncommon relationship is reviewed. CONCLUSION: Premature closure of posterior fossa sutures as part of Crouzon's syndrome can present with large sinus pericranii. Such subcutaneous swellings might resolve spontaneously.
Subject(s)
Craniofacial Dysostosis/pathology , Sinus Pericranii/pathology , Humans , Infant , MaleABSTRACT
BACKGROUND: Infants with craniofacial dysostosis syndromes may present with midface abnormalities but without major (calvarial) suture synostosis and head shape anomalies. Delayed presentation of their calvarial phenotype is known as progressive postnatal craniosynostosis. Minor sutures/synchondroses are continuations of major sutures toward and within the skull base. The authors hypothesized that minor suture synostosis is present in infants with syndromic, progressive postnatal craniosynostosis, and is associated with major suture synostosis. METHODS: The authors performed a two-institution review of infants (<1 year) with syndromic craniosynostosis and available computed tomographic scans. Major (i.e., metopic, sagittal, coronal, and lambdoid) and minor suture/synchondrosis fusion was determined by two craniofacial surgeons and one radiologist using Mimics or Radiant software. RESULTS: Seventy-three patients with 84 scans were included. Those with FGFR2 mutations were more likely to lack any major suture fusion (OR, 19.0; p = 0.044). Minor suture fusion occurred more often in the posterior branch of the coronal arch (OR, 3.33; p < 0.001), squamosal arch (OR, 7.32; p < 0.001), and posterior intraoccipital synchondroses (OR, 15.84; p < 0.001), among FGFR2 versus other patients. Patients (n = 9) with multiple scans showed a pattern of minor suture fusion followed by increased minor and major suture synostosis. Over 84 percent of FGFR2 patients had minor suture fusion; however, six (13 percent) were identified with isolated major suture synostosis. CONCLUSIONS: Minor suture fusion occurs in most patients with FGFR2-related craniofacial dysostosis. Syndromic patients with patent calvarial sutures should be investigated for minor suture involvement. These data have important implications for the pathophysiology of skull growth and development in this select group of patients. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III.
Subject(s)
Cranial Sutures/pathology , Craniofacial Dysostosis/pathology , Craniosynostoses/pathology , Craniofacial Dysostosis/physiopathology , Craniosynostoses/genetics , Craniosynostoses/physiopathology , Female , Humans , Infant , Intracranial Pressure/physiology , Male , Receptor, Fibroblast Growth Factor, Type 2/genetics , Tomography, X-Ray ComputedABSTRACT
PURPOSE: Midface distraction osteogenesis has been popularized for the correction of midface hypoplasia associated with exophthalmos and obstructive sleep apnea in patients with Crouzon syndrome. The purpose of this study was to present the method of utilizing the modified external device with elastic distraction for the midface advancement in Crouzon syndrome, and the clinical outcomes and skeletal changes were analyzed. METHODS: Five consecutive patients with Crouzon syndrome underwent Le Fort III osteotomy with midface advancement using a modified external device with elastic distraction. The distraction system consists of a rigid external distractor, nickel-titanium shape memory alloy spring, and bone-borne traction hooks. The midface advancement was initiated with the bony anchorage around the nasomaxillary buttress at the level between occlusal plane and infraorbital margin. The device was activated at a rate of 1 to 1.5âmm per day by the length of spring. The skeletal changes were analyzed by cephalometric and computed tomographic measurement. RESULTS: All the patients achieved improvements in midface appearance, obstructive sleep apnea, exophthalmos, and occlusion. No complications occurred during this procedure. After the distraction, 1 patient developed an open bite that was corrected by a definitive orthognathic surgery. Cephalometric and computed tomographic measurement analysis showed a differential advancement of midface with more at the occlusal level than the orbital level. In addition, midface suture and bone remodeling was also observed in growing patient. CONCLUSIONS: Our modified external device with elastic distraction offers an alternative method to achieve midface advancement in patients with Crouzon syndrome.