Nonsyndromic Craniosynostosis Patients Research Articles

Intraoperative intracranial pressure monitoring in the pediatric craniosynostosis population.

OBJECTIVEEvaluation of increased intracranial pressure (ICP) in the pediatric craniosynostosis population based solely on ophthalmological, clinical, and radiographic data is subjective, insensitive, and inconsistent. The aim of this study was to examine the intraoperative ICP before and after craniectomy in this patient population.METHODSThe authors measured the ICP before and after craniectomy using a subdural ICP monitor in 45 children. They regulated end-tidal carbon dioxide and the monitoring site under general anesthesia to record consistent ICP readings.RESULTSThe average age of the patient population was 29 months (range 3.8-180.5 months). Thirty-seven patients (82.2%) were undergoing initial craniosynostosis procedures. All craniosynostosis procedures were categorized as one of the following: frontoorbital advancement (n = 24), frontoorbital advancement with distraction osteogenesis (n = 1), posterior vault distraction osteogenesis (n = 10), and posterior vault reconstruction (n = 10). Nineteen of 45 patients (42.2%) had syndromic or multisuture craniosynostosis. The mean postcraniectomy ICP (8.8 mm Hg, range 2-18 mm Hg) was significantly lower than the precraniectomy ICP (16.5 mm Hg, range 6-35 mm Hg) (p < 0.001). Twenty-four patients (53%) had elevated ICP prior to craniectomy, defined as ≥ 15 mm Hg. Only 4 (8.9%) children had papilledema on preoperative funduscopic examination (sensitivity 17%, specificity 100%, negative predictive value 51%, and positive predictive value 100%). There were no significant differences in elevated precraniectomy ICP based on type of craniosynostosis (syndromic/multisuture or nonsyndromic) or age at the time of surgery. Patients undergoing initial surgery in the first 12 months of life were significantly less likely to have elevated precraniectomy ICP compared with patients older than 12 months (26.3% vs 73.1%, p = 0.005).CONCLUSIONSIn this study, the authors report the largest cohort of syndromic and nonsyndromic craniosynostosis patients (n = 45) who underwent precraniectomy and postcraniectomy ICP evaluation. A craniectomy or completed craniotomy cuts for distractors effectively reduced ICP in 43/45 patients. The authors' findings support the notion that papilledema on funduscopy is a highly specific, however poorly sensitive, indicator of increased ICP, and thus is not a reliable screening method. These findings indicate that even nonsyndromic patients with craniosynostosis are at risk for increased ICP. Furthermore, patients who present prior to 12 months of age appear less likely to have elevated ICP on presentation. Further studies with other noninvasive imaging of the retina may be useful as an adjunct tool for determining elevated ICP.

Quality of Life in Adults with Nonsyndromic Craniosynostosis.

Although studies have analyzed quality of life in children with nonsyndromic craniosynostosis, to date nobody has investigated long-term quality of life in adults with nonsyndromic craniosynostosis. The purpose of this study was to compare quality of life in adult nonsyndromic craniosynostosis patients with a cohort of unaffected controls. The authors queried their institution's prospectively maintained craniofacial registry for nonsyndromic craniosynostosis patients aged 18 years and older, and administered the validated World Health Organization Quality of Life Biomedical Research and Education Foundation questionnaire. Responses were compared, using a two-sample t test, to an age-matched U.S. normative database provided by the World Health Organization. One hundred fifty-one adults met inclusion criteria: 52 were successfully contacted and 32 completed the questionnaire. Average age of respondents was 23.0 ± 6.1 years (range, 18.1 to 42.1 years). Nonsyndromic craniosynostosis patients had a superior quality of life compared with comparative norms in all domains: physical health (17.8 ± 2.7 versus 15.5 ± 3.2; p < 0.001), psychological (16.3 ± 2.9 versus 13.8 ± 3.2; p < 0.001), social (16.9 ± 2.6 versus 13.2 ± 3.6; p < 0.001), and environmental (17.2 ± 2.5 versus 11.7 ± 2.7; p < 0.001). Comparison between single-suture subtypes revealed no difference in any quality-of-life domain (p > 0.05). Adult patients previously treated for nonsyndromic craniosynostosis perceive their quality of life to be high, superior to that of a normative U.S. Future work will seek to analyze additional patients and better understand the reasons behind these findings.

Overactive autophagy is a pathological mechanism underlying premature suture ossification in nonsyndromic craniosynostosis

Nonsyndromic craniosynostosis (NSC) is the most common craniosynostosis with the primary defect being one or more fused sutures. In contrast to syndromic craniosynostosis, the etiopathogenesis of NSC is largely unknown. Here we show that autophagy, a major catabolic process required for the maintenance of bone homeostasis and bone growth, is a pathological change associated with NSC. Using calvarial suture mesenchymal cells (SMCs) isolated from the fused and unfused sutures of NSC patients, we demonstrate that during SMC differentiation, the level of the autophagosomal marker LC3-II increases as osteogenic differentiation progresses, particularly at differentiation day 7, a stage concurrent with mineralization. In fused SMCs, autophagic induction was more robust than that in unfused SMCs, which consequently led to enhanced mineralized nodule formation. Perturbation of autophagy with rapamycin or wortmannin promoted or inhibited the ossification of SMCs, respectively. Our findings suggest that autophagy is essential for the osteogenic differentiation of SMCs and that overactive autophagy is a molecular abnormality underlying premature calvarial ossification in NSC.

The Etiology of Neuronal Development in Craniosynostosis: A Working Hypothesis.

Craniosynostosis is one of the most common craniofacial conditions treated by neurologic and plastic surgeons. In addition to disfigurement, children with craniosynostosis experience significant cognitive dysfunction later in life. Surgery is performed in infancy to correct skull deformity; however, the field is at a crossroads regarding the best approach for correction. Since the cause of brain dysfunction in these patients has remained uncertain, the role and type of surgery might have in attenuating the later-observed cognitive deficits through impact on the brain has been unclear. Recently, however, advances in imaging such as event-related potentials, diffusion tensor imaging, and functional MRI, in conjunction with more robust clinical studies, are providing important insight into the potential etiologies of brain dysfunction in syndromic and nonsyndromic craniosynostosis patients. This review aims to outline the cause(s) of such brain dysfunction including the role extrinsic vault constriction might have on brain development and the current evidence for an intrinsic modular developmental error in brain development. Illuminating the cause of brain dysfunction will identify the role of surgery can play in improving observed functional deficits and thus direct optimal primary and adjuvant treatment.

Genome-Wide Association Study in Craniosynostosis Condition Using Innovative Systematic Bioinformatic Analysis Tools and Techniques: Future Prospective and Clinical Practice.

Background:Craniosynostosis (CS) conditions are included with the premature fusion of one or more multiple cranial sutures. As the second leading and most common craniofacial anomaly and orofacial clefts globally. Syndromic and nonsyndromic CS (NSCS) occur as a part of a genetic syndrome unlike Apert, Crouzon, Pfeiffer, Muenke, and Saethre–Chotzen syndromes. Approximately, 90% of the cases of CS arises from NSCS group and it is now a great challenge for the researcher and neurosurgeon for Indian-origin children, a great burden worldwide.Material and Methods:Study design: Prospective study of analysis sequence pattern on CS and NSCS from January 2007 to 2018 was carried out.Inclusion criteria: Diagnosed cases in syndromic and NSCS patients between 3 months and 14 years of age either preoperative or postoperative were included in the study of both groups (syndromic and NSCS).Exclusion criteria: Patients with primary microcephaly (secondary CS), postural plagiocephaly, incomplete data, no visual perception, and who were lost to follow-up, and who had no interest to participate the study were excluded from the study.Bioinformatic analysis: We have performed systematic bioinformatic analysis for all responsible genes by combining with using through the GeneDecks, Gene Runner, DAVID, and STRING databases.Genes testing: FGF family genes, MSX genes, such as Irf6, TP63, Dlx2, Dlx5, Pax3, Pax9, Bmp4, Tgf-beta2, and Tgf-beta3 were found to be involved in Cleft lip and cleft palate (CL/P), and Fgfr2, Fgfr1, Fgfr3, and TWIST, MSX, MSX1, 2 were found to be involved in both the groups of CS (SCS + NSCS).Results:FGFR, MSX, Irf6, TP63, Dlx2, Dlx5, Pax3, Pax9, Bmp4, Tgf-beta2, and Tgf-beta3 demonstrated and find out that in CL/P, and Fgfr2, Fgfr1, Fgfr3, and Twist1 had accurate sequence data with more than accuracy of 95% reported with proper order with additional anomalies CS through newly developed tools.Conclusion:Newly developed techniques of GeneDecks, Gene Runner, DAVID, and STRING databases gave better picture to analyze the larger population, patients (SCS + NSCS) with complex genetic, maternal, parental age, environmental, and stochastic factors contributing to NSCS networking, signaling, and pathways involvement. This bioinformatic tools analyzed better prediction of CS and NSCS sequences guiding us the newer invention modalities of pattern of screening and further development of recent future application.

Impact of Fronto-Orbital Advancement on Frontal Sinus Volume, Morphology, and Disease in Nonsyndromic Craniosynostosis.

Fronto-orbital advancement for nonsyndromic craniosynostosis has been thought to injure frontal sinus buds, lead to chronic sinus disease, and influence final forehead shape. This study investigates the effect of fronto-orbital advancement in infancy on subsequent frontal sinus volume, morphology, and disease. The authors conducted a retrospective review of nonsyndromic craniosynostosis patients treated with fronto-orbital advancement in infancy with a head computed tomographic scan obtained at age 7 to 18 years. Facial trauma patients served as age-matched controls. Frontal sinus characteristics were determined using three-dimensional reconstructions. The study included 33 nonsyndromic craniosynostosis patients who underwent fronto-orbital advancement (n = 20 unicoronal; n = 13 metopic) and 20 control patients. The incidence of at least unilateral pneumatization was 94 percent for fronto-orbital advancement subjects and 95 percent for control subjects. Mean frontal sinus volumes for unicoronal synostosis, metopic synostosis, and control groups were 3427 ± 2294, 4576 ± 3510, and 4157 ± 3963 mm, respectively (p = 0.598). Asymmetry scores were as follows: unicoronal synostosis, 56 ± 35 percent; metopic synostosis, 36 ± 33 percent; and control, 23 ± 24 percent (p = 0.010). Unicoronal subjects displayed prominent asymmetry, with increased pneumatization on the unaffected side. Frontal sinus volume correlated with age at computed tomography but not with age at fronto-orbital advancement. Interrater reliability was 0.997. One fronto-orbital advancement subject and zero control subjects demonstrated computed tomographic evidence of frontal sinus disease. Frontal sinus volume, morphology, and disease do not differ significantly between control subjects and nonsyndromic craniosynostosis subjects following fronto-orbital advancement, but subtle differences such as increased asymmetry in the unicoronal synostosis group can be appreciated. Further research with syndromic craniosynostosis patients undergoing multiple procedures may help elucidate the association between surgical disruption and frontal sinus development. Therapeutic, III.

Mutation Screening of Candidate Genes in Patients with Nonsyndromic Sagittal Craniosynostosis.

Craniosynostosis is a condition that includes the premature fusion of one or multiple cranial sutures. Among various craniosynostosis forms, sagittal nonsyndromic craniosynostosis is the most prevalent. Although different gene mutations have been identified in some craniosynostosis syndromes, the cause of sagittal nonsyndromic craniosynostosis remains largely unknown. To screen for candidate genes for sagittal nonsyndromic craniosynostosis, the authors sequenced DNA of 93 sagittal nonsyndromic craniosynostosis patients from a population-based study conducted in Iowa and New York states. FGFR1-3 mutational hotspots and the entire TWIST1, RAB23, and BMP2 coding regions were screened because of their known roles in human nonsyndromic or syndromic sagittal craniosynostosis, expression patterns, and/or animal model studies. The authors identified two rare variants in their cohort. A FGFR1 insertion c.730_731insG, which led to a premature stop codon, was predicted to abolish the entire immunoglobulin-like III domain, including the ligand-binding region. A c.439C>G variant was observed in TWIST1 at its highly conserved loop domain in another patient. The patient's mother harbored the same variant and was reported with jaw abnormalities. These two variants were not detected in 116 alleles from unaffected controls or seen in the several databases; however, TWIST1 variant was found in a low frequency of 0.000831 percent in Exome Aggregation Consortium database. The low mutation detection rate indicates that these genes account for only a small proportion of sagittal nonsyndromic craniosynostosis patients. The authors' results add to the perception that sagittal nonsyndromic craniosynostosis is a complex developmental defect with considerable genetic heterogeneity. Risk, II.

The Management of Blood Loss in Non-Syndromic Craniosynostosis Patients Undergoing Barrel Stave Osteotomy.

Barrel stave osteotomy is a widely used procedure in neurosurgery for the majority of craniosynostosis patients. Both in the intraoperative and postoperative periods, there is inevitable leakage type bleeding from the bones undergoing osteotomy. A number of studies have been performed in order to prevent this complication but a concise procedure is still lacking. Synostectomy and parietotemporal barrel stave osteotomy were applied to 143 patients who were operated on with a diagnosis of craniosynostosis between the years 2005-2013. At the beginning to osteotomy, 5 ml/kg erythrocyte suspension (ES) was given for probable blood loss. Whole blood count was performed at the postoperative 1st and 6th hours and cases with hemoglobin levels below 10 or with hematocrit levels which had decreased more than 5% between the 1st and 6th hours were administered erythrocyte transfusion. Of the patients, 100 were boys and 43 were girls. Of these, 98 had metopic, 30 had sagittal, 9 had metopic+sagittal, 4 had unilateral, 2 had bilateral and 6 had coronal synostosis. All the cases were administered intraoperative erythrocyte suspension. The preoperative amount of administered mean erythrocyte was 8.61 ml/kg. In the postoperative period, 92 patients were administered erythrocyte suspension. The postoperative amount of administered mean erythrocyte suspension was 7.98 ml/kg. For an operated infant with craniosynostosis who is operated on in the first year of life, undergoing osteotomy and inevitable bone-borne blood losses are very important and these have to be replaced immediately.

Clinicogenetic Study of Turkish Patients With Syndromic Craniosynostosis and Literature Review

BackgroundFibroblast growth factor receptor 2 mutations have been associated with the craniosynostotic conditions of Apert, Crouzon, Pfeiffer, Saethre-Chotzen, Jackson-Weiss, Beare-Stevenson cutis gyrata, and Antley-Bixler syndromes in various ethnic groups. MethodsThirty-three unrelated Turkish patients (12 with Apert syndrome, 14 with Crouzon syndrome, six with Pfeiffer syndrome, and one with Saethre-Chotzen syndrome) and 67 nonsyndromic craniosynostosis patients were screened for mutations in exons IIIa and IIIc of the FGFR2 gene by denaturing high-performance liquid chromatography and confirmed by direct sequencing. ResultsWe detected several pathogenic mutations in 11/33 (33%) patients with Apert syndrome (four with p.Pro253Arg; seven with p.Ser252Trp) and 8/33 (24%) patients with Crouzon syndrome (three with p.Trp290Arg, one with p.Cys342Tyr, p.Cys278Phe, p.Gln289Pro, and a novel p.Tyr340Asn mutation) and five (15%) with Pfeiffer syndrome (p.Cys342Arg, p.Pro253Arg, p.Trp290Arg, and p.Ser351Cys). No FGFR2 gene mutation was detected in any of the patients with Saethre-Chotzen syndrome and nonsyndromic craniosynostosis. ConclusionsOur results indicate that the majority of Turkish patients with syndromic craniosynostosis have detectable genetic changes with an overall frequency of 72.7%. Because this is the first molecular genetic report from a Turkish cohort, the identified spectrum profile of FGFR2 mutations of the syndromic craniosynostotic patients would be very helpful for understanding the genotype–phenotype relationship and has a great value for diagnosis, prognosis, and genetic counseling.

Methylenetetrahydrofolate reductase C677T variant in Indian children with craniosynostosis: Its role in the pathogenesis, risk of craniosynostosis.

BACKGROUND:677C to T allele in the 5, 10-methylenetetrahydrofolate reductase (MTHFR) gene has been implicated in the etiology of various syndromes and nonsyndromic diseases but till date no direct studies have been reported with craniosynostosis.OBJECTIVES:The aim was to study the family-based association of MTHFR polymorphism in different categories of craniosynostosis patients.MATERIALS AND METHODS:This was a cross-sectional study in which 30 patients classified as Apert syndrome, Pfeiffr syndrome and nonsyndromic craniosynostosis patients with their family were recruited. A sample of 3 ml intravenous blood was taken from patients and from their family members (father and mother) in ethylenediaminetetraacetic acid-anticoagulated vacutainer for the purpose of the study. Genomic DNA was extracted from peripheral blood lymphocytes by phenol chloroform extraction method. Primers for MTHFR gene were designed. The polymerase chain reaction was carried out. After successful amplification, a small aliquot (5 μl) of the MTHFR reaction mixture was treated with 1 units of Hinf I restriction enzyme (NEB). Results were obtained and compiled.RESULTS:A total of 30 patients/participants with craniosynostosis of Indian descent and their parents formed the study group. The genotyping did not confirm an association between the MTHFR 677C to T polymorphism and between different categories of craniosynostosis. When comparing the offspring of mothers statistically significant differences were found.CONCLUSION:C667T polymorphism of the MTHFR gene is unlikely to play a role in the pathogenesis of craniosynostosis though maternal MTHFR C677T polymorphism may be a genetic risk factor.

Familial incidence and associated symptoms in a population of individuals with nonsyndromic craniosynostosis

Craniosynostosis is a common cranial malformation occurring in 1 per 2,000-2,500 births. Isolated defects (nonsyndromic) occur in ~75% of cases and are thought to have multifactorial etiology. It is believed that each suture synostosis is a distinct disease, with varying phenotypes and recurrence rates. We analyzed family histories of 660 mutation-negative nonsyndromic craniosynostosis patients and symptoms in 189 of these patients. The incidence rate of craniosynostosis was highest for first-degree relatives of probands with metopic craniosynostosis (6.4%), followed by those with complex craniosynostosis (4.9%), sagittal craniosynostosis (3.8%), lambdoid craniosynostosis (3.9%), and coronal craniosynostosis (0.7%). Across all suture types, siblings had a greater craniosynostosis incidence rate than parents (7.5 vs. 2.3%). In phenotype comparisons, patients with complex craniosynostosis had the highest frequency of reported symptoms and those with sagittal craniosynostosis had the lowest. Ear infections, palate abnormalities, and hearing problems were more common in complex craniosynostosis patients. Visual problems were more common in coronal craniosynostosis, and metopic craniosynostosis patients noted increased frequency of chronic cough. Our data suggest that the genetic component of nonsyndromic craniosynostosis appears to be suture specific. The incidence rate of craniosynostosis among first-degree relatives varies by suture and family member. Additionally, the phenotype of each suture synostosis shows both unique and shared features.

Temporal Morphomics as a Model for Determining Preoperative Risk of Blood Transfusion in Nonsyndromic Craniosynostosis Patients

Estimates of blood loss during craniosynostosis surgeries have ranged from 42 to 126 percent of infant's total blood volume. Currently, no risk model has been developed to determine the likelihood of needing a blood transfusion. The authors propose an objective model, based on patients' three-dimensional anatomical characteristics, to stratify the likelihood of needing perioperative packed red blood cells. High-throughput image analysis from already ordered preoperative computed tomographic scans was used to reconstruct the three-dimensional anatomy of the temporalis muscle and overlying temporal fat pad. Using these morphomic measurements, the authors created a risk assessment model of the amount of packed red blood cells infused based on morphomic variations in temporal soft tissue. The authors evaluated 139 infants with nonsyndromic craniosynostosis from the University of Michigan Health System. Results show the need for blood transfusion ranged from 94.1 percent among patients in the smallest quartile for temporal fat pad volume compared with 65.7 percent among the group with the largest quartile for temporal fat pad volume (p = 0.0057). Using multivariable linear regression, temporal fat pad volume (p = 0.012) and fat pad thickness (p = 0.036) were independent predictors for amount of packed red blood cells required. The authors demonstrate that patients with diminished temporal fat pad volume are significantly more likely to need increased packed red blood cell transfusions. In addition, by use of multivariable linear regression, their data suggest that temporal fat pad volume and thickness were independent predictors for the amount of required transfusion of packed red blood cells.

Temporal morphomics as a model for aiding preoperative risk of blood transfusion in non-syndromic craniosynostosis patients

Temporal morphomics as a model for aiding preoperative risk of blood transfusion in non-syndromic craniosynostosis patients

Novel Temporalis Muscle and Fat Pad Morphomic Analyses Aids Preoperative Risk Evaluation and Outcome Assessment in Nonsyndromic Craniosynostosis

Analytical morphomics is the term we created to describe an innovative, highly automated, anatomically indexed processing of 3D medical imaging data captured during the course of a patients' preoperative CT scan. Our specific aim is to determine the efficacy of craniofacial morphomic indices (CMI) such as temporalis muscle and temporal fat pad morphometric values to predict blood transfusion requirement and hospital stay in a cohort of children with nonsyndromic craniosynostosis (NSC). High-throughput, semi-automated image analysis was used to reconstruct the 3-dimensional anatomy of the temporalis muscle and temporal fat pad and to quantify CMIs. The prognostic effect of CMI on clinical outcomes were evaluated among all NSC patients and compared across various craniosynostosis subtypes using Wilcoxon nonparametric tests and Kendall's τ to determine significance. Using preoperative CT images, we evaluated 117 children with NSC from the University of Michigan Health System. Results demonstrate that increased temporal fat pad volume and local temporalis muscle volume are associated with better clinical outcomes in craniosynostosis patients. More specifically, temporal fat pad volume was shown to be a significant predictor of perioperative blood transfusion requirements (P = 0.0033) and increased temporal muscle volume correlated with decreased hospital stay (P = 0.016) when controlling for other covariates including age, sex, weight, and preoperative hematocrit. In addition, the same significant predictors were found when examining individual subtypes of craniosynostosis. Our findings demonstrate that maxillofacial CT scans provide a useful quantitative index reflecting general patient health, risk stratification, and probabilities of intervention in addition to their previously established ability to determine the specific pathology of the patient. We demonstrate that temporal morphomics predict the incidence of blood transfusion, hospital stay, and serve as a proxy for fitness in patients undergoing craniosynostosis surgery.

Morphometric comparison of foramen magnum in non-syndromic craniosynostosis patients with or without Chiari I malformation

In order to compare the morphometry of foramen magnum (FM) in a matched-pair study, in children with non-syndromic craniosynostosis with and without Chiari I malformation (CMI), both brain magnetic resonance (MRI) and multidetector computed tomography (MDCT) images were utilized. Brain MR images were retrieved from the Helsinki University Hospital Picture Archiving and Communications System to identify patients with CMI during 1.1.2004 to 31.3.2009. Age-, gender-, and craniosynostosis-matched controls were retrieved from the same cohort. Morphometric analysis of FM was carried out. Seven patients with non-syndromic craniosynostosis with CMI were recorded. In CMI patients, the absolute anteroposterior length was 33.4 mm as compared to 36.7 mm in controls (p = 0.023). The mean width was 28.1 and 29.9 mm (p = 0.29), and the cross-sectional area was 654.1 and 764.9 mm(2) (p = 0.11) in CMI and controls, respectively. In CMI patients, the relative anteroposterior length of the FM was, on average, 91 % of the control's measurements. On average, the width was 95 % and the cross-sectional area was 88 % of the control's results. In pediatric non-syndromic craniosynostosis patients, a statistically significant reduced anteroposterior diameter of the FM is found in patients with an adjacent CMI as compared to their age-, gender-, and type-matched controls of craniosynostosis.

Genetic basis of potential therapeutic strategies for craniosynostosis

Craniosynostosis, the premature fusion of one or more cranial sutures, is a common malformation of the skull that can result in facial deformity and increased intracranial pressure. Syndromic craniosynostosis is present in ∼15% of craniosynostosis patients and often is clinically diagnosed by neurocranial phenotype as well as various other skeletal abnormalities. The most common genetic mutations identified in syndromic craniosynostosis involve the fibroblast growth factor receptor (FGFR) family with other mutations occurring in genes for transcription factors TWIST, MSX2, and GLI3, and other proteins EFNB1, RAB23, RECQL4, and POR, presumed to be involved either upstream or downstream of the FGFR signaling pathway. Both syndromic and nonsyndromic craniosynostosis patients require early diagnosis and intervention. The premature suture fusion can impose pressure on the growing brain and cause continued abnormal postnatal craniofacial development. Currently, treatment options for craniosynostosis are almost exclusively surgical. Serious complications can occur in infants requiring either open or endoscopic repair and therefore the development of nonsurgical techniques is highly desirable although arguably difficult to design and implement. Genetic studies of aberrant signaling caused by mutations underlying craniosynostosis in in vitro calvarial culture and in vivo animal model systems have provided promising targets in designing genetic and pharmacologic strategies for systemic or adjuvant nonsurgical treatment. Here we will review the current literature and provide insights to future possibilities and limitations of therapeutic applications.

Internal Distraction Osteogenesis to Correct Symptomatic Cephalocranial Disproportion

Cephalocranial disproportion describes a state of volume mismatch between brain size and intracranial space. Nonsyndromic single-suture craniosynostosis patients can present with symptoms from elevated intracranial pressure because of inadequate or delayed treatment. The purpose of this study was to present five sagittal synostosis children with symptomatic cephalocranial disproportion treated with cranial vault distraction osteogenesis. Asymmetric transverse internal distraction osteogenesis was performed to preferentially expand the posterior cranium. A wider base plate, pivot screw, anterior hinge plate, and flexible drive rod were applied to minimize device failure while accomplishing lateral rotation of parietal bones. A distraction protocol was developed and produced consistent results. Two girls and three boys underwent distraction for sagittal synostosis between 2002 and 2006. Average age at surgery was 5.8 years. All had resolution or amelioration of preoperative symptoms. Average operating room time for distractor placement was 2.5 hours (152 minutes) and average hospital stay was 2.8 days. The average distracted distance was 14.4 mm. Average operating room time for distractor removal was 1.1 hours (69 minutes) and average hospital stay was 1.6 days. No perioperative complications occurred. Average follow-up period was 4.2 years, with no recurrence of symptoms. Symptomatic cephalocranial disproportion can present in older children with craniosynostosis. Asymmetric transverse distraction of the posterior cranial vault is a safe and effective treatment modality for this population.

Unravelling the molecular control of calvarial suture fusion in children with craniosynostosis

BackgroundCraniosynostosis, the premature fusion of calvarial sutures, is a common craniofacial abnormality. Causative mutations in more than 10 genes have been identified, involving fibroblast growth factor, transforming growth factor beta, and Eph/ephrin signalling pathways. Mutations affect each human calvarial suture (coronal, sagittal, metopic, and lambdoid) differently, suggesting different gene expression patterns exist in each human suture. To better understand the molecular control of human suture morphogenesis we used microarray analysis to identify genes differentially expressed during suture fusion in children with craniosynostosis. Expression differences were also analysed between each unfused suture type, between sutures from syndromic and non-syndromic craniosynostosis patients, and between unfused sutures from individuals with and without craniosynostosis.ResultsWe identified genes with increased expression in unfused sutures compared to fusing/fused sutures that may be pivotal to the maintenance of suture patency or in controlling early osteoblast differentiation (i.e. RBP4, GPC3, C1QTNF3, IL11RA, PTN, POSTN). In addition, we have identified genes with increased expression in fusing/fused suture tissue that we suggest could have a role in premature suture fusion (i.e. WIF1, ANXA3, CYFIP2). Proteins of two of these genes, glypican 3 and retinol binding protein 4, were investigated by immunohistochemistry and localised to the suture mesenchyme and osteogenic fronts of developing human calvaria, respectively, suggesting novel roles for these proteins in the maintenance of suture patency or in controlling early osteoblast differentiation. We show that there is limited difference in whole genome expression between sutures isolated from patients with syndromic and non-syndromic craniosynostosis and confirmed this by quantitative RT-PCR. Furthermore, distinct expression profiles for each unfused suture type were noted, with the metopic suture being most disparate. Finally, although calvarial bones are generally thought to grow without a cartilage precursor, we show histologically and by identification of cartilage-specific gene expression that cartilage may be involved in the morphogenesis of lambdoid and posterior sagittal sutures.ConclusionThis study has provided further insight into the complex signalling network which controls human calvarial suture morphogenesis and craniosynostosis. Identified genes are candidates for targeted therapeutic development and to screen for craniosynostosis-causing mutations.