Suture Fusion Research Articles

Ultrasonography as first line imaging for the diagnosis of positional plagiocephaly.

In the last years, numerous studies evaluated different tools for the diagnosis of positional plagiocephaly (PP). The purpose of this study was to evaluate ultrasonography (US) as a first line screening test of lambdoid sutural patency in child with PP and to compare our results with the literature. All consecutive patients who referred to our Institute from January 2016 to October 2017 with the suspicion of PP, were included in the study and performed US examination of the lambdoid sutures. A 3-6-month clinical follow-up was performed by a pediatric neurosurgeon or a pediatrician to confirm the diagnosis of PP. Thirty-five children performed US examination and in all cases the diagnosis of PP was confirmed. No cases of anticipated suture fusion were examined during this period. The concordance between US findings and clinical exam follow-up was 100%. Ultrasonography of the lambdoid sutures represents an ideal first-line screening test and reliable alternative to other diagnostic techniques for lambdoid sutural patency in child with PP, being radiation free, fast and cheap.

Unravelling the pathogenesis of foramen magnum stenosis in patients with severe achondroplasia: a CT-based comparison with age-matched controls and FGFR3 craniosynostosis syndromes.

Foramen magnum(FM) stenosis can be responsible for acute and chronic damage to the cervicomedullary junction in children with achondroplasia. The bony anatomy and patterns of suture fusion of the FM in this context are incompletely understood, yet becoming increasingly important in the light of novel medical therapies for achondroplasia. The objective of this study was to describe and quantify bony anatomy and fusion patterns of FM stenosis in patients with achondroplasia using CT scans, comparing them to age-matched controls and other FGFR3 craniosynostosis patients. Patients with achondroplasia and severe FM stenosis, classified as achondroplasia foramen magnum score(AFMS) grades 3 and 4, were identified from a departmental operative database. All had pre-operative CT scans of the craniocervical junction. Measurements obtained comprised sagittal diameter (SD), transverse diameter (TD), foramen magnum area, and opisthion thickness. Anterior and posterior interoccipital synchondroses (AIOS and PIOS) were graded by the extent of fusion. These measurements were then compared with CT scans from 3 age-matched groups: the normal control group, children with Muenke syndrome, and children with Crouzon syndrome with acanthosis nigricans (CSAN). CT scans were reviewed in 23 cases of patients with achondroplasia, 23 normal controls, 20 Muenke, and 15 CSAN. Children with achondroplasia had significantly smaller sagittal diameter (mean 16.2 ± 2.4mm) compared to other groups (control 31.7 ± 2.4mm, p < 0.0001; Muenke 31.7 ± 3.5mm, p < 0.0001; and CSAN 23.1 ± 3.4mm, p < 0.0001) and transverse diameters (mean 14.3 ± 1.8mm) compared with other groups (control 26.5 ± 3.2mm, p < 0.0001; Muenke 24.1 ± 2.6mm, p < 0.0001; CSAN 19.1 ± 2.6mm, p < 0.0001). This translated into a surface area which was 3.4 times smaller in the achondroplasia group compared with the control group. The median grade of the AIOS fusion achondroplasia group was 3.0 (IQR 3.0-5.0), which was significantly higher compared with the control group (1.0, IQR 1.0-1.0, p < 0.0001), Muenke group (1.0, IQR 1.0-1.0, p < 0.0001), and CSAN (2.0, IQR 1.0-2.0, p < 0.0002). Median PIOS fusion grade was also highest in the achondroplasia group (5.0, IQR 4.0-5.0) compared with control (1.0, IQR 1.0-1.0, p < 0.0001), Muenke (2.5, IQR 1.3-3.0, p < 0.0001), and CSAN (4.0, IQR 4.0-4.0, p = 0.2). Distinct bony opisthion spurs projecting into the foramen magnum were seen in achondroplasia patients but not others, resulting in characteristic crescent and cloverleaf shapes. Patients with AFMS stages 3 and 4 have significantly reduced FM diameters, with surface area 3.4 times smaller than age-matched controls. This is associated with premature fusion of the AIOS and PIOS in comparison with controls and other FGFR3-related conditions. The presence of thickened opisthion bony spurs contributes to stenosis in achondroplasia. Understanding and quantifying bony changes at the FM of patients with achondroplasia will be important in the future quantitative evaluation of emerging medical therapies.

Radiomorphologic profiles of nonsyndromic sagittal craniosynostosis

PurposeNumerous classification systems of nonsyndromic sagittal craniosynostosis (NSC) are applied but none has gained a wide acceptance, since each classification is focused on distinct aspects of cranial dysmorphology. The goal of this study was to depict the most common combinations of radiomorphologic characteristics of NSC and to separate groups where the patients were morphologically similar to one another and at the same time significantly different from others.MethodsThe study was conducted on anonymized thin-cut CT scans of 131 children with NSC aged 1–12 months (mean age 5.42 months). The type of cranial dysmorphology was assessed using four criteria: skull shape, pattern of sagittal suture fusion, morphologic features and cerebrospinal fluid (CSF) spaces alterations. After assigning the categories, an unsupervised k-modes clustering algorithm was applied to identify distinct patients clusters representing radiomorphologic profiles determined by investigated characteristics.ResultsCluster analysis revealed three distinct radiomorphologic profiles including the most common combinations of features. The profiles were not influenced by sex nor age but were significantly determined by skull shape (V = 0.58, P < 0.0001), morphologic features (V = 0.50, P < 0.0001) and pattern of sagittal suture fusion (V = 0.47, P < 0.0001). CSF alterations did not significantly correlate with the profiles (P = 0.3585).ConclusionNSC is a mosaic of radiologic and morphologic features. The internal diversity of NSC results in dissimilar groups of patients defined by unique combinations of radiomorphologic characteristics, from which the skull shape is the most differentiating factor. Radiomorphologic profiles support the idea of clinical trials targeted at more selective outcomes assessment.

KDM6A Mediated Regulation of Cranial Frontal Bone Suture Fusion in Mice is Sex-Dependent.

The five flat bones of developing cranial plates are bounded by fibrous sutures, which remain open during development to accommodate for the growing brain. Kdm6A is a demethylase which removes the epigenetic repressive mark, tri-methylated lysine 27 on histone 3 (H3K27me3), from the promoters of osteogenic genes, and has previously been reported to promote osteogenesis in cranial bone cells. The present study generated a mesenchyme-specific deletion of a histone demethylase, Kdm6a, to assess the effects of Kdm6a loss, in cranial plate development and suture fusion. The results showed that the loss of Kdm6a in Prx-1+ cranial cells caused increased anterior width and length in the calvaria of both male and female mice. However, the posterior length was further decreased in female mice. Moreover, loss of Kdm6a resulted in suppression of late suture development and calvarial bone formation predominantly in female mice. In vitro assessment of calvaria cultures isolated from female Kdm6a knockout mice, found significantly suppressed calvarial osteogenic differentiation potential, associated with decreased gene expression levels of Runx2 and Alkaline Phosphatase and increased levels of the suppressive mark, H3K27me3 on the respective gene promoters. Conversely, cultured calvaria bone cultures isolated from male Kdm6a knockout mice exhibited an increased osteogenic differentiation potential. Interestingly, the milder effects on cranial suture development in Kdm6a knockout male mice, were associated with an overcompensation of the Kdm6a Y-homolog, Kdm6c and increased expression levels of Kdm6b in calvarial bone cultures. Taken together, these data demonstrate a role for Kdm6a during calvarial development and patterning, predominantly in female mice, and highlights the potential role of Kdm6 family members in patients with unexplained craniofacial deformities.

Calvarial Vault Remodeling Technique for Lambdoid Craniosynostosis.

Premature fusion of the lambdoid suture is the most uncommon single-suture synostosis. It presents with a classic "windswept" appearance, a trapezoid-shaped head, and significant skull asymmetry notable for an ipsilateral mastoid bulge and contralateral frontal bossing. Because of the rarity of lambdoid synostosis, little is known about optimal techniques for its treatment. In particular, the proximity of the lambdoid suture to critical intracranial structures such as the superior sagittal and transverse sinuses represents a potential for significant intraoperative bleeding. Prior work has shown that parietal asymmetry persists after repair in these cases. In this article, the authors present a technique for the treatment of unilateral lambdoid craniosynostosis along with two representative cases. This calvarial vault remodeling technique requires the removal of both ipsilateral and contralateral parietal bones. These are moved across hemispheres and reinset on opposite sides to help correct the parietal asymmetry. Obliquely orientated barrel stave osteotomies are performed to provide a safe mechanism for correction of occipital flattening. The authors' early results show improvement in correction of volume asymmetry 1 year postoperatively relative to patients treated with prior calvarial vault remodeling techniques. The authors believe the technique presented here corrects the windswept appearance in patients with lambdoid craniosynostosis and also reduces the potential for complications. Further work will be necessary to confirm this technique's long-term efficacy in a larger cohort.

Correlation between degree of sagittal suture fusion and surrogates of elevated intracranial pressure in sagittal craniosynostosis.

Sagittal craniosynostosis constricts transverse skull growth, with possible neurocognitive sequelae. While the degree of sagittal suture fusion has been shown to influence the degree of dysmorphology, it is unknown if it impacts functional findings, including elevated intracranial pressure (ICP). The purpose of this study was to determine associations between the degree of sagittal suture fusion and optical coherence tomography (OCT) surrogates suggestive of increased ICP in patients with nonsyndromic sagittal craniosynostosis. Three-dimensional CT head images of patients with sagittal craniosynostosis were analyzed in Materialise Mimics and parietal bones were manually isolated to determine the percentage fusion of the sagittal suture. Retinal OCT was performed prior to the cranial vault procedure with analysis for thresholds that correlate with elevated ICP. The degree of sagittal suture fusion was compared with OCT retinal parameter measurements using Mann-Whitney U-tests, Spearman's correlations, and multivariate logistic regression models controlled for age. Forty patients (31 males) with nonsyndromic sagittal craniosynostosis at a mean (± SD) age of 3.4 ± 0.4 months were included in this study. OCT surrogates of elevated ICP (maximal retinal nerve fiber layer [RNFL] thickness and maximal anterior projection [MAP]) were not associated with total sagittal suture fusion (p > 0.05). Maximal RNFL thickness was positively associated with increased percentage of posterior one-half (rho = 0.410, p = 0.022) and posterior one-third (rho = 0.417, p = 0.020) sagittal suture fusion. MAP was also positively associated with increased percentage of posterior one-half (rho = 0.596, p < 0.001) and posterior one-third (rho = 0.599, p < 0.001) sagittal suture fusion. Multivariate logistic regression models revealed increased percentage of posterior one-half (p = 0.048) and posterior one-third (p = 0.039) sagittal suture fusion predicted ICP > 20 mm Hg. Increased percentage fusion of the posterior sagittal suture, but not total suture, was positively associated with retinal changes indicative of increased ICP. These findings suggest suture fusion leading to increased ICP may be region specific.

A clinician's perspective on indications and failures of bone-borne maxillary expanders

With the increasing popularity of bone-borne maxillary expansion in conferences, social media and publications, the promotion of the procedure may outpace the availability of high-quality evidence, leading to potential biases in its use. This paper offers a clinician's perspective on indications and failures in different age groups and stresses the importance of prioritizing diagnostics over appliance-centered treatment. Understanding individual variations in sutural fusion or similar diagnostic strategies will be increasingly crucial in identifying the appropriate expansion method. Depending on the patient's maturation stage, different types of expanders may be employed, utilizing various anchorage strategies, such as permanent or deciduous tooth-borne, bone-borne, hybrid, or surgically assisted expanders. The article provides clinical examples, discussing limited indications and age-related risk factors, and highlights failures to emphasize the importance of a patient-centered approach to treatment.

Differential morphometric analysis of the anterior fontanelle in an embryonic avian model of induced-thyrotoxicosis.

Craniosynostosis (CS) is the premature fusion of the cranial sutures during embryonic development, and this results in intracranial pressure and skull deformities. Thyrotoxicosis, specifically maternal hyperthyroidism, has been linked to the development of CS. Our lab is currently validating an avian model of thyroxine-induced CS to study the mechanism involved in thyroxine-enhanced cranial ossification. We hypothesized that thyroxine exposure will alter skull morphology. Two groups of fertilized chicken eggs were injected with saline or 25 ng T4 into the air cell on embryonic days (E) 11 and 15. A set of skulls from each group were collected on E17-19 (n = 17-21/day). They were fixed in formalin and processed using Alizarin Red whole-mount staining, imaged (superior view), and quantified to determine thyroxine-induced alteration in skull morphology. Geometric morphometric analysis using MorphoJ was performed to identify shape variation between treatment groups of the fibrous space between ossifying regions of the anterior fontanelle. These preliminary results demonstrated a significant variation in the shape of the fibrous gap between developing sutures on embryonic days 17, 18, and 19 (p&lt;0.05). Using the same methodology, an additional set of skulls on E19 were collected from each group and processed using both Alizarin red and Alcian blue whole-mount staining to better delineate the ossifying region of bone. Analysis is currently in progress. In conclusion, these findings support that our model is successful in promoting the fusing of the cranial bones with thyroxine exposure in our avian model through altered skull morphology visualized in the anterior fontanelle.

Surgical Management of Craniosynostosis—Between the Past and the Future: A Comprehensive Review of the Literature

AbstractCranial sutures are fibrous joints between the bones of the cranial vault, acting as centers of osteogenesis of the embryonic mesenchyme. Skull growth is a strictly regulated process, controlled by several genetic pathways. A minor perturbation of these pathways may lead to premature fusion of the cranial sutures. Craniosynostosis occurs as a result of the premature fusion of the cranial sutures. The incidence of craniosynostosis is approximately 1 in 2,500 live births. Syndromic craniosynostoses such as Apert, Crouzon, and Pfeiffer comprise 15% of patients, while nonsyndromic craniosynostosis represents 85% of all patients. By the late 1800s, Lannelongue (Paris, 1890) and Lane (San Francisco, 1892) attempted the first surgical intervention (strip craniectomy) for the management of craniosynostosis. The inadequacy of simple suturectomies and strip craniectomies in the management of craniosynostosis led to the innovation of more complex procedures such as frontoorbital advancement and posterior cranial vault distraction. However, these extensive surgical interventions are lengthy procedures and associated with more blood volume loss which requires blood transfusion. These limitations led to the modern era of minimally invasive endoscopic techniques. In this paper, we reviewed the body of the literature on the evolution of surgical management of craniosynostosis over the last century and the possible future directions.

A new juvenile sauropod specimen from the Middle Jurassic Dongdaqiao Formation of East Tibet.

Jurassic strata are widely distributed in the eastern part of Tibet Autonomous Region, and have yielded many dinosaur bones. However, none of these specimens has been studied extensively, and some remain unprepared. Here we provide a detailed description of some new sauropod material, including several cervical vertebrae and a nearly complete scapula, recovered from the Middle Jurassic of Chaya County, East Tibet. The cervical vertebrae have short centra that bear ventral midline keels, as in many non-neosauropod sauropods such as Shunosaurus. Moreover, the cervical centra display deep lateral excavations, partitioned by a septum. The scapula has proximal and distal ends that are both expanded as in mamenchisaurids and neosauropods. However, relatively small body size and lack of fusion of neurocentral sutures in the cervical vertebrae suggest that the available material is from a juvenile, and the length of the cervical centra may have increased relative to the size of the rest of the skeleton in later ontogenetic stages. Phylogenetic analysis provides limited evidence that the new Tibetan sauropod specimen belongs to Eusauropoda, being more derived than Shunosaurus, but is basal to Mamenchisauridae. The new material provides important information on the morphological transition between Shunosaurus and mamenchisaurids, and extends the known biogeographic range of early-diverging sauropods in the Middle Jurassic of East Asia.

Fusion of Lateral Calvarial Sutures on Volume-Rendered Computed Tomography Reconstructions in Patients With Known Craniosynostosis.

After treating a child with familial sagittal craniosynostosis, clinocephaly, and bilateral parietomastoid/posterior squamosal suture fusion, the authors wondered if major-suture synostosis and clinocephaly were associated with abnormal fusion of minor lateral calvarial sutures. The authors reviewed all preoperative volume-rendered head computed tomography reconstructions performed for craniosynostosis at their institution from 2010 through 2014 and determined whether the sphenoparietal, squamosal, and parietomastoid sutures were open, partially fused, or fused. The authors determined whether any sutures were abnormally fused based upon a previous study from their center, in which abnormal fusion was defined as either 1 of 3 abnormal fusion patterns or abnormally-early fusion. The authors then determined the rate of abnormal fusion of these sutures and whether abnormal fusion was associated with (1) major-suture craniosynostosis, (2) type of craniosynostosis (sutures involved; single-suture versus multisuture; syndromic versus nonsyndromic), and (3) clinocephaly. In 97 included children, minor lateral sutures were abnormally fused in 8, or 8.2%, which was significantly higher than in children without craniosynostosis from our earlier study. Abnormal minor lateral suture fusion was not associated with the type of single-suture synostosis or with multisuture synostosis but was associated with syndromic synostosis. Four of 8 children with abnormal minor lateral suture fusion had multisuture synostosis and 6 had syndromic synostosis. Lateral sutures were abnormally fused in 1 of 4 subjects with clinocephaly, which was not significant. Abnormal minor lateral calvarial suture fusion is significantly associated with major-suture craniosynostosis, especially syndromic synostosis.

Orbital Foraminal Morphometrics in Nonsyndromic Unilateral Coronal Craniosynostosis.

Nonsyndromic unilateral coronal craniosynostosis (UCS) is a rare congenital disorder that results from premature fusion of either coronal suture. The result is growth restriction across the suture, between the ipsilateral frontal and parietal bones, leading to bony dysmorphogenesis affecting the calvarium, orbit, and skull base. Prior studies have reported associations between UCS and visual abnormalities. The present study utilizes a novel geometric morphometric analysis to compare dimensions of orbital foramina on synostotic versus nonsynostotic sides in patients with UCS. Computed tomography head scans of pediatric UCS patients were converted into 3-dimensional mesh models. Anatomical borders of left and right orbital structures were plotted by a single trained team member. Dimensions between synostotic and nonsynostotic sides were measured and compared. Medical records were examined to determine prevalence of visual abnormalities in this patient cohort. Visual abnormalities were reported in 22 of the 27 UCS patients (77.8%). Astigmatism (66.7%), anisometropic amblyopia (44.4%), and motor nerve palsies (33.3%) represented the 3 most prevalent ophthalmologic abnormalities. Orbits on synostotic sides were 11.3% narrower ( P < 0.001) with 21.2% less volume ( P = 0.028) than orbits on nonsynostotic sides. However, average widths, circumferences, and areas were similar between synostotic and nonsynostotic sides upon comparison of supraorbital foramina, infraorbital foramina, optic foramina, and foramina ovalia. Therefore, previously proposed compression or distortion of vital neurovascular structures within bony orbital foramina does not seem to be a likely etiology of visual abnormalities in UCS patients. Future studies will examine the role of ocular and/or neuro-ophthalmologic pathology in this disease process.

The Paediatric Vault Score (PVS)-A Novel Scoring Tool for Prioritisation of Surgical Management of Craniosynostosis Patients.

Craniosynostosis is the premature fusion of the skull sutures, resulting in abnormal skull shape and volume. Timely management is a priority in avoiding raised intracranial pressure which can result in blindness and neurodevelopmental delay. Due to the COVID-19 pandemic, theater access was reduced. A risk stratification scoring system was thus devised to score patients attending surgery and aid in prioritization according to surgical need. The authors present the Paediatric Vault Score (PVS), which can also be customized to each unit's individual protocols. Ten patients on the waiting list were randomly selected and their clinical information was summarized in uniform anonymized reports. Six craniofacial consultants were selected as assessors and given 1 week to independently rank the patients from 1 to 10. Each scorer's ranking was verified against the PVS template and concordance was analyzed using the Kendall tau correlation coefficient (KT). Three cycles of the scoring process were carried out. Improvements were made to the scoring tool following cycle 1. Cycle 1 revealed 2 clinicians to be concordant with the PVS system and 4 to be discordant. Cycle 2 revealed all 6 clinicians to be concordant, with a mean KT score of 0.61. The final cycle revealed all 6 clinicians to be concordant, with a mean KT score of 0.70. Four scorers increased their concordance once the scoring sheet was introduced. Kendall's correlation of concordance calculated the interrater reliability to be 0.81. The PVS is the first known vault scoring system to aid in risk stratification and waiting list prioritization.

Craniosynostosis in Patients With X-Linked Hypophosphatemia: A Review.

Craniosynostosis is a rare condition of skull development, manifesting during fetal and early infant development, and is usually congenital. Craniosynostosis secondary to metabolic disorders, such as X-linked hypophosphatemia (XLH), is less common and is typically diagnosed later than congenital craniosynostosis. XLH is a rare, progressive, and lifelong hereditary phosphate-wasting disorder characterized by loss of function of the phosphate-regulating endopeptidase homologue, X-linked gene, which is associated with premature fusion of cranial sutures due to abnormal phosphate metabolism (hypophosphatemia) and altered bone mineralization or elevated levels of fibroblast growth factor 23. This targeted literature review of 38 articles seeks to provide an overview of craniosynostosis in individuals with XLH. The objectives of this review are to increase awareness of the prevalence, presentation, and diagnosis of craniosynostosis in XLH; examine the spectrum of craniosynostosis severity in XLH; discuss the management of craniosynostosis in those with XLH; recognize the complications for patients with XLH; and identify what is known about the burden of craniosynostosis for individuals with XLH. The presentation of craniosynostosis in individuals with XLH tends to manifest slightly later than congenital craniosynostosis and can vary in severity and appearance, making diagnosis difficult and resulting in inconsistent clinical outcomes. Consequently, craniosynostosis in patients with XLH is an underreported and potentially underrecognized condition. There have been no studies investigating the effects of craniosynostosis on the quality of life of people with XLH. Despite a growing awareness among researchers and experienced clinicians, there are still improvements to be made in general awareness and timely diagnosis of craniosynostosis in XLH. The XLH community would benefit from further study into the prevalence of craniosynostosis, the effect of XLH medical therapy on the development of craniosynostosis, and the effects of craniosynostosis on quality of life. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Long-term neurocognitive outcomes in 204 single-suture craniosynostosis patients.

Craniosynostosis, which describes premature fusion of one or more cranial sutures, has been associated with a variety of neurocognitive deficits. We sought to explore the cognitive profiles of the various types of single-suture, non-syndromic craniosynostosis (NSC). A retrospective review of children 6-18 years old with surgically corrected NSC who underwent neurocognitive testing (Weschler Abbreviated Scale of Intelligence, Beery-Buktenica Developmental Test of Visuomotor Integration) from the years 2014-2022 was conducted. 204 patients completed neurocognitive testing (139 sagittal, 39 metopic, 22 unicoronal, 4 lambdoid suture). 110 (54%) of the cohort was male, and 150 (74%) were White. Mean IQ was 106.10±14.01 and mean age at surgery and testing were 9.0±12.2 months and 10.9±4.0 years, respectively. Sagittal synostosis was associated with higher scores than metopic synostosis, with significant differences in verbal IQ (109.42±15.76 vs 101.37±10.41), full-scale IQ (108.32±14.44 vs 100.05±11.76), visuomotor integration (101.62±13.64 vs 92.44±12.07), visual perception (103.81±12.42 vs 95.87±11.23), and motor coordination (90.45±15.60 vs 84.21±15.44). Sagittal synostosis was associated with significantly higher scores for visuomotor integration (101.62±13.64 vs 94.95±10.24) and visual perception (103.81±12.42 vs 94.82±12.75) than unicoronal synostosis. Compared to patients with sagittal synostosis, patients with metopic synostosis exhibited lower scores in verbal IQ, full-scale IQ, visuomotor integration, visual perception, and motor control after surgical correction. Despite surgical correction for premature metopic suture fusion, the effect on the adjacent frontal lobe and white matter connections to other regions of the brain may have a lasting functional impact. Patients with unicoronal synostosis exhibited lower visuomotor integration and visual perception scores.

Augmentation of BMP Signaling in Cranial Neural Crest Cells Leads to Premature Cranial Sutures Fusion through Endochondral Ossification in Mice.

Craniosynostosis is a congenital anomaly characterized by the premature fusion of cranial sutures. Sutures are a critical connective tissue that regulates bone growth; their aberrant fusion results in abnormal shapes of the head and face. The molecular and cellular mechanisms have been investigated for a long time, but knowledge gaps remain between genetic mutations and mechanisms of pathogenesis for craniosynostosis. We previously demonstrated that the augmentation of bone morphogenetic protein (BMP) signaling through constitutively active BMP type 1A receptor (caBmpr1a) in neural crest cells (NCCs) caused the development of premature fusion of the anterior frontal suture, leading to craniosynostosis in mice. In this study, we demonstrated that ectopic cartilage forms in sutures prior to premature fusion in caBmpr1a mice. The ectopic cartilage is subsequently replaced by bone nodules leading to premature fusion with similar but unique fusion patterns between two neural crest-specific transgenic Cre mouse lines, P0-Cre and Wnt1-Cre mice, which coincides with patterns of premature fusion in each line. Histologic and molecular analyses suggest that endochondral ossification in the affected sutures. Both in vitro and in vivo observations suggest a greater chondrogenic capacity and reduced osteogenic capability of neural crest progenitor cells in mutant lines. These results suggest that the augmentation of BMP signaling alters the cell fate of cranial NCCs toward a chondrogenic lineage to prompt endochondral ossification to prematurely fuse cranial sutures. By comparing P0-Cre;caBmpr1a and Wnt1-Cre;caBmpr1a mice at the stage of neural crest formation, we found more cell death of cranial NCCs in P0-Cre;caBmpr1a than Wnt1-Cre;caBmpr1a mice at the developing facial primordia. These findings may provide a platform for understanding why mutations of broadly expressed genes result in the premature fusion of limited sutures. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Spectrum of ocular manifestations in apert syndrome

Apert syndrome is a congenital type 1 acrocephalosyndactyly characterized by craniosynostosis, dysmorphic facial features and symmetrical syndactyly. There is premature fusion of cranial sutures which leads to restriction of intracranial and orbital space expansion giving characteristic dysmorphic facial appearance. We are reporting two cases of Apert syndrome of different age groups from ophthalmic point of view, and with different sets of ocular manifestation. Of the two cases, the one who presented early had a better visual prognosis. Apert Syndrome has a social stigma and the patients often suffers social and psychological disturbances. Patient counselling, timely management by multidisciplinary approach and regular follow ups are an important aspect which can offer a better quality of life.

Impact of Minor Suture Fusion on Midface Hypoplasia in Syndromic Craniosynostosis

Purpose: Early onset of minor suture fusion in syndromic craniosynostosis is associated with midface dysplasia and is a common indication for craniofacial surgery. However, the potential effects of fusion severity on craniofacial growth patterns are not well understood. This study seeks to describe the impact of minor suture fusion severity on midface morphology in Crouzon syndrome. Methods: Pre-operative computed tomography images (CT) of 63 patients with Crouzon syndrome and 63 normocepahlic controls were included. Degree of suture fusion was assessed for the frontosphenoidal, sphenethmoidal, sphenosquamosal, sphenopetrosal, spheno-occipital synchondrosis, frontoethmoidal, and zygomaticosphenoidal sutures. Each suture was graded on a 5-point scale. The sella (S), nasion (N), A point (A), basion (BA), and anterior nasal spine (ANS) landmarks were used to calculate the SNA angle, BA-ANS length of the lower midface, and N-S length of the upper midface. Multiple linear regressions were used to analyze data. Results: The mean age was 43 months and 44% were female. The control group was significantly older ( P &lt; .01) than the patients with Crouzon syndrome. Advanced fusion of the spheno-occipital synchondrosis in Crouzon syndrome correlates with regression of the BA-ANS length by 0.563 mm per incremental increase in suture fusion ( P &lt; .01). Additionally, the lower midface (BA-ANS) was restricted to a greater degree than the upper midface (N-S) with progressive suture fusion in all patient types with ratios of these rates ranging between 0.602 and 0.89 for the 7 sutures analyzed. Suture fusion severity did not impact the SNA angle in any of the analyses performed. Conclusion: The severity of sheno-occipital synchondrosis fusion in Crouzon syndrome contributes to midface hypoplasia. Similarly, all anterior skull base sutures limited lower midface growth to a greater degree than the upper midface.

Practical Algorithm for the Management of Multisutural Craniosynostosis with Associated Chiari Malformation and/or Hydrocephalus

Introduction: The association between multisutural craniosynostosis with Chiari malformation (CM), venous hypertension, and hydrocephalus is widely described in the literature, especially in children with paediatric craniofacial syndromes. Some efforts have been done in the last years to understand the complex pathogenetic mechanisms underlying this association, and several theories have been proposed. In particular, it is now accepted that the hypothesis of the overcrowding of the posterior fossa due to precocious suture fusion is the cause of the cerebellar herniation in syndromic and non-syndromic patients, against the theory of intrinsic cerebellar anomalies, ventriculomegaly, and venous hypertension. However, whatever the pathophysiological mechanism, it is still unclear what the best management and treatment of CM and hydrocephalus are in multisutural craniosynostosis patients. The aim of this study was to report our 25 years’ experience in treating paediatric patients affected by these rare pathologies in order to propose a simple and effective therapeutic flow chart for their management. Materials and Methods: We retrospectively collected data of each patient who underwent a cranial vault remodelling (CVR) for complex multisutural craniosynostosis in our institution in the last 25 years, while monosutural craniosynostosis was excluded. We recorded data concerning type of craniosynostosis and craniofacial syndromes, presence of ventriculomegaly, and CM at presentation and clinical and radiological follow-up. Therefore, we evaluated the final outcomes (improved, stable, deteriorated) of these patients and created a practical flow chart that could help physicians choose the best surgical treatment when different pathological conditions, as Chiari malformation I (CMI) or hydrocephalus, affect complex craniosynostosis children. Results: Thirty-nine patients (39 out of 55; 70.9%), with an isolated multisutural craniosynostosis at presentation, underwent a two-step CVR as first surgery; 36 patients (92.3%) had an improved outcome, 2 patients (5.1%) had a stable outcome, and 1 patient (2.56%) had a deteriorated outcome. Other eight children (8 out of 55; 14.5%) had a radiological evidence of asymptomatic CMI at presentation. In this group, we performed CVR as first surgery. As for the final outcome, 7 patients had an improved outcome (87.5%) with good aesthetic result and stability or resolution of CMI. Finally, 7 patients (7 out of 55; 12.7%) presented a various combination of CMI and ventriculomegaly or hydrocephalus at presentation. Among them, 3 patients had an improved outcome (42.8%), and 4 patients had a deteriorated outcome (57.1%). Discussion: The prevalence of one pathological condition with associated symptoms over the others was the key factor leading our therapeutic strategy. When craniosynostosis is associated with a radiological CM, the assessment of clinical symptoms is of capital importance. When asymptomatic or pauci-symptomatic, we suggest a CVR as first step, for its efficacy in reducing tonsillar herniation and solving CM symptoms. When craniosynostosis is associated with ventricular enlargement, the presence of intracranial hypertension signs and symptoms forces physicians to first treat hydrocephalus with a ventriculo-peritoneal shunt or endoscopic third ventriculostomy. For patients with various degrees and severity of ventriculomegaly and associated CM, the outcomes were very heterogeneous, even when the same therapeutic strategy was applied to patients with similar starting conditions and symptoms. This is maybe the most unexpected and least clear part of our results. Despite the proposed algorithm comes from a clinical experience on 85% successfully treated patients with multiple craniosynostosis, more extensive and deep studies are needed to better understand CM and hydrocephalus development in such conditions.

Augmentation of bone morphogenetic protein signaling in cranial neural crest cells in mice deforms skull base due to premature fusion of intersphenoidal synchondrosis.

Craniofacial anomalies (CFAs) are a diverse group of disorders affecting the shapes of the face and the head. Malformation of the cranial base in humans leads CFAs, such as midfacial hypoplasia and craniosynostosis. These patients have significant burdens associated with breathing, speaking, and chewing. Invasive surgical intervention is the current primary option to correct these structural deficiencies. Understanding molecular cellular mechanism for craniofacial development would provide novel therapeutic options for CFAs. In this study, we found that enhanced bone morphogenetic protein (BMP) signaling in cranial neural crest cells (NCCs) (P0-Cre;caBmpr1a mice) causes premature fusion of intersphenoid synchondrosis (ISS) resulting in leading to short snouts and hypertelorism. Histological analyses revealed reduction of proliferation and higher cell death in ISS at postnatal day 3. We demonstrated to prevent the premature fusion of ISS in P0-Cre;caBmpr1a mice by injecting a p53 inhibitor Pifithrin-α to the pregnant mother from E15.5 to E18.5, resulting in rescue from short snouts and hypertelorism. We further demonstrated to prevent premature fusion of cranial sutures in P0-Cre;caBmpr1a mice by injecting Pifithrin-α through E8.5 to E18.5. These results suggested that enhanced BMP-p53-induced cell death in cranial NCCs causes premature fusion of ISS and sutures in time-dependent manner.