Cranial sutures.

Cranial sutures are not of great concern to the modern neurosurgeon, except when abnormalities interfere with the skull's shape and its ability to expand during childhood. It is a commonplace that a craniotomy may cross a variety of sutures without providing any extra difficulty to the operator. The sagittal suture does remain useful as a definition of the midline of the cranium and as an indicator of the underlying sinus. Galen for reasons that are far from clear, "observed" relationships between the sutures, the meninges and the pericranium which led him to advise avoidance of any surgical proximity to the sutures. The result of this proscription was a severe limit of the access surgeons considered was appropriate and thus limited their ability to care for their patients.

Ultrasonic mapping of midpalatal suture - An ex-vivo study.

OBJECTIVE: Rapid maxillary expansion is a common orthodontic procedure to correct maxillary constriction. Assessing the midpalatal suture (MPS) expansion plays a crucial role in treatment planning to determine its effectiveness. The objectives of this preliminary investigation are to demonstrate a proof of concept that the palatal bone underlying the rugae can be clearly imaged by ultrasound (US) and the reconstructed axial view of the US image accurately maps the MPS patency. METHODS: An ex-vivo US scanning was conducted on the upper jawbones of two piglet's carcasses before and after the creation of bone defects, which simulated the suture opening. The planar images were processed to enhance bone intensity distribution before being orderly stacked to fuse into a volume. Graph-cut segmentation was applied to delineate the palatal bone to generate a bone volume. The accuracy of the reconstructed bone volume and the suture opening was validated by the micro-computed tomography (µCT) data used as the ground truth and compared with cone beam computed tomography (CBCT) data as the clinical standard. Also included in the comparison is the rugae thickness. Correlation and Bland-Altman plots were used to test the agreement between the two methods: US versus µCT/CBCT. RESULTS: The reconstruction of the US palatal bone volumes was accurate based on surface topography comparison with a mean error of 0.19 mm for pre-defect and 0.15 mm and 0.09 mm for post-defect models of the two samples, respectively when compared with µCT volumes. A strong correlation (R2 ≥ 0.99) in measuring MPS expansion was found between US and µCT/CBCT with MADs of less than 0.05 mm, 0.11 mm and 0.23 mm for US, µCT and CBCT, respectively. CONCLUSIONS: It was possible to axially image the MPS opening and rugae thickness accurately using high-frequency ultrasound. CLINICAL SIGNIFICANCE: This study introduces an ionizing radiation-free, low-cost, and portable technique to accurately image a difficult part of oral cavity anatomy. The advantages of conceivable visualization could promise a successful clinical examination of MPS to support the predictable treatment outcome of maxillary transverse deficiency.

Transcriptomic and cellular decoding of scaffolds-induced suture mesenchyme regeneration.

Precise orchestration of cell fate determination underlies the success of scaffold-based skeletal regeneration. Despite extensive studies on mineralized parenchymal tissue rebuilding, regenerating and maintaining undifferentiated mesenchyme within calvarial bone remain very challenging with limited advances yet. Current knowledge has evidenced the indispensability of rebuilding suture mesenchymal stem cell niches to avoid severe brain or even systematic damage. But to date, the absence of promising therapeutic biomaterials/scaffolds remains. The reason lies in the shortage of fundamental knowledge and methodological evidence to understand the cellular fate regulations of scaffolds. To address these issues, in this study, we systematically investigated the cellular fate determinations and transcriptomic mechanisms by distinct types of commonly used calvarial scaffolds. Our data elucidated the natural processes without scaffold transplantation and demonstrated how different scaffolds altered in vivo cellular responses. A feasible scaffold, polylactic acid electrospinning membrane (PLA), was next identified to precisely control mesenchymal ingrowth and self-renewal to rebuild non-osteogenic suture-like tissue at the defect center, meanwhile supporting proper osteointegration with defect bony edges. Especially, transcriptome analysis and cellular mechanisms underlying the well-orchestrated cell fate determination of PLA were deciphered. This study for the first time cellularly decoded the fate regulations of scaffolds in suture-bony composite defect healing, offering clinicians potential choices for regenerating such complicated injuries.

Performance of dental students, orthodontic residents, and orthodontists for classification of midpalatal suture maturation stages on cone-beam computed tomography scans - a preliminary study.

BACKGROUND: Assessment of midpalatal suture maturation on cone-beam computed tomography (CBCT) scans is performed by visual inspection and is therefore subjective. The extent to which the assessment of midpalatal suture maturation is affected by rater experience has not been adequately explored in the existing literature, thus limiting the availability of evidence-based findings. This study compared the outcomes of classification by dental students, orthodontic residents, and orthodontists. METHODS: Three different groups of students, orthodontic residents, and orthodontists evaluated 10 randomly chosen CBCT scans regarding midpalatal suture maturation from a pool of 179 patients (98 female and 81 male patients) aged 8 - 40 years which were previously classified by evaluating CBCT scans. The pool was set as benchmark utilizing midpalatal suture maturation classification by one examiner (OsiriX Lite version 11.0; Pixmeo SARL, Bernex, Switzerland). For assessment of intra-rater reliability of the examiners of each group the randomly chosen subjects were reclassified for midpalatal suture maturation after a wash-out period of two weeks by using the same software. Statistical analysis was performed to evaluate intra- and interrater reliability of the three groups with differing experience level. RESULTS: Groupwise intra-rater reliability assessment between the classification and reclassification was weak for examiners with a low level of experience (k = 0.59). Orthodontists had highest degree of agreement with regard to benchmark classification with an inter-rater reliability to be considered as moderate (k = 0.68). CONCLUSIONS: Assessment of midpalatal suture maturation on CBCT scans appears to be a subjective process and is considerably related to the experience level of the examiner. A high level of clinical experience seems to be favorable but does not necessarily ensure accurate results.

Fractality of Cranial Sutures.

It has long been known that skull suture has a typical fractal structure. Although the fractal dimension has been utilized to assess morphology, the mechanism of the fractal structure formation remains to be elucidated. Recent advances in the mathematical modeling of biological pattern formation provided useful frameworks for understanding this mechanism. This chapter describes how various proposed mechanisms tried to explain the formation of fractal structures in cranial sutures.

Association of cranial base suture/synchondrosis fusion with severity of increased intracranial pressure in Crouzon syndrome.

This study investigated how the fusion states of the cranial base is related to the degree of increased intracranial pressure (ICP) in patients with Crouzon syndrome. This retrospective cohort study enrolled patients who were diagnosed with Crouzon syndrome between May 2007 and April 2022. We categorized the patients into three groups: A, B, and C, according to the severity of increased ICP and the number of cranial vault remodeling procedures for corrective operation. The preoperative fusion states of the cranial base sutures/synchondroses were examined using facial bone computed tomography and compared between groups. Overall, 22 patients were included in Groups A, B, and C, including 8, 7, and 7 patients, respectively. The preoperative average grades of the total cranial base suture/synchondrosis fusion appeared to significantly increase with severity, except for the frontoethmoidal suture, which showed the opposite tendency. In the subgroup analysis, frontosphenoidal, sphenoparietal, sphenosquamosal, parietomastoid, and occipitomastoid suture and petro-occipital synchondrosis were associated with earlier fusion in the more severe group. Premature closure of the cranial base sutures/synchodroses seems to be associated with increased ICP severity in patients with Crouzon syndrome. Precise evaluation of minor sutures/synchondroses at the first visit might help build subsequent operative plans and predict disease prognosis.

Cranial suture lineage and contributions to repair of the mouse skull.

The cranial sutures are proposed to be a stem cell niche, harbouring skeletal stem cells that are directly involved in development, homeostasis and healing. Like the craniofacial bones, the sutures are formed from both mesoderm and neural crest. During cranial bone repair, neural crest cells have been proposed to be key players; however, neural crest contributions to adult sutures are not well defined, and the relative importance of suture proximity is unclear. Here, we use genetic approaches to re-examine the neural crest-mesoderm boundaries in the adult mouse skull. These are combined with calvarial wounding experiments suggesting that suture proximity improves the efficiency of cranial repair. Furthermore, we demonstrate that Gli1+ and Axin2+ skeletal stem cells are present in all calvarial sutures examined. We propose that the position of the defect determines the availability of neural crest-derived progenitors, which appear to be a key element in the repair of calvarial defects.

The effect of vertical skeletal proportions, skeletal maturation, and age on midpalatal suture maturation: a CBCT-based study.

BACKGROUND: Midpalatal suture (MPS) maturation may be influenced by a range of parameters including age, gender, and vertical skeletal pattern. We therefore aimed to evaluate the effect of Frankfurt-mandibular angle (FMA), skeletal maturation, and age on the timing of MPS maturation. METHODS: In this cross-sectional study, cone-beam computed tomography (CBCT) and lateral cephalograms were used to assess the MPS and cervical vertebral maturation (CVM) stage. A proportional odds logistic regression model was used to assess associations between age adjusted for gender and MPS maturation, and a regression analysis was performed to analyze the effect of vertical pattern on these associations. RESULTS: A total of 201 patients (84 male and 117 female) with a mean age of 13.48 (SD 1.94) were included. With increasing age, the odds of belonging to a higher maturation stage increased (OR: 2.14; 95% CI 1.789; 2.567; P < 0.001); however, no association between FMA and MPS maturation was observed (OR: 1.01; 95% CI 0.964; 1.051; P = 0.76). A strong correlation between MPS maturation and CVM stage was not reported. Males had a higher probability of belonging to a lower MPS maturation stage (OR: 0.24; 95% CI 0.136; 0.415; P < 0.001). CONCLUSIONS: Based on this cross-sectional analysis, midpalatal sutural maturation classification is associated with chronological age and occurs later in males. Neither CVM staging nor variation in vertical skeletal proportions were useful predictors of midpalatal maturation stage.

Unreported variant foramen of the frontal bone: the latero-orbital foramen.

Variant foramina of the skull can lead to misdiagnosis on medical imaging and potentially, intraoperative complications if not appreciated. Here, we report an unusual foramen found superior to the frontozygomatic suture. The foramen was located on the left side at the superolateral rim of the orbit, 2.36 cm inferolateral to the supraorbital foramen. It was positioned 2.5 mm superior to the frontozygomatic suture. The foramen had a length of 3.1 mm and a width of 1.3 mm. The internal opening of the foramen was located 1.45 cm superolateral to the zygomaticotemporal foramen. We suggest that this foramen is a pathway for either a branch of the zygomatic nerve or lacrimal nerve and/or their vascular bundles. Although the prevalence of such a finding cannot be confirmed, such a case is of archival value as a comparison for future similar cases.

Are the Ethmoidal Foramina Through the Frontal Bone, Ethmoid Bone, or Frontoethmoidal Suture?

INTRODUCTION: To investigate the locations of the anterior, middle, and posterior ethmoidal foramina and their relationships to the frontoethmoidal suture. METHODS: One hundred twenty sides from sixty adult human skulls were used. Specimens with significant damage to the medial orbit wall were excluded. The number of ethmoidal foramina (anterior, middle, and posterior) on the medial orbital wall and the relationship of each foramen to the frontoethmoidal suture were recorded and classified as follows: Type I: superior to the frontoethmoidal suture; Type II: on the frontoethmoidal suture; Type III: inferior to the frontoethmoidal suture. RESULTS: Of the ninety-four sides, fourteen (14.9%) had one foramen, sixty-two (66.0%) had two , and eighteen (19.1%) had three. In total, 192 ethmoidal foramina were observed. Among the fourteen sides with one foramen, eight foramina were anterior and six were posterior. Among the 192 ethmoidal foramina, 162 were eligible for fur ther classification (74 anterior, 14 middle, and 74 posterior). Types I, II, and III ethmoidal foramina were found in 38.3% (62/162), 61.7% (100/162), and 0% (0/162), respectively. CONCLUSIONS: Our current study found a higher incidence of type I than previously reported. It is important to be aware of the significant incidence of foramen variations when the medial orbit wall is manipulated during surgery. Unless caution is observed, an inadvertent surgical injury can occur and lead to life-threatening complications. Therefore, a good understanding of orbital anatomy and its potential variations is critical for improving patient out comes.

Multiscale mechanical characterisation of the craniofacial system under external forces.

Premature fusion of craniofacial joints, i.e. sutures, is a major clinical condition. This condition affects children and often requires numerous invasive surgeries to correct. Minimally invasive external loading of the skull has shown some success in achieving therapeutic effects in a mouse model of this condition, promising a new non-invasive treatment approach. However, our fundamental understanding of the level of deformation that such loading has induced across the sutures, leading to the effects observed is severely limited, yet crucial for its scalability. We carried out a series of multiscale characterisations of the loading effects on normal and craniosynostotic mice, in a series of in vivo and ex vivo studies. This involved developing a custom loading setup as well as software for its control and a novel in situ CT strain estimation approach following the principles of digital volume correlation. Our findings highlight that this treatment may disrupt bone formation across the sutures through plastic deformation of the treated suture. The level of permanent deformations observed across the coronal suture after loading corresponded well with the apparent strain that was estimated. This work provides invaluable insight into the level of mechanical forces that may prevent early fusion of cranial joints during the minimally invasive treatment cycle and will help the clinical translation of the treatment approach to humans.

What can a morphometric study of unoperated children teach us about the natural history of metopic synostosis?

OBJECTIVE: Outcomes of surgical repair of trigonocephaly are well reported in the literature, but there is a paucity of information on the natural history of unoperated children. The authors evaluated a group of unoperated children with metopic synostosis to describe the natural change in head shape over time. METHODS: A database was screened for scans of children with unoperated trigonocephaly (2010-2021). Multisuture cases and those with a metopic ridge were excluded. Three-dimensional surface scans (3D stereophotogrammetry/CT) were used for morphological analysis. Nine previously published parameters were used: frontal angle (FA30°), anteroposterior (AP) volume ratio (APVR), AP area ratio (APAR), AP width ratios 1 and 2 (APWR1 and APWR2), and 4 AP diagonal ratios (30° right APDR [rAPDR30], 30° left APDR [lAPDR30], 60° right APDR [rAPDR60], and 60° left APDR [lAPDR60]). RESULTS: Ninety-seven scans were identified from a cohort of 316 patients with a single metopic suture, in which the male-to-female ratio was 2.7:1. Ages at the time of the scan ranged from 9 days to 11 years and were stratified into 4 groups: group 1, < 6 months; group 2, 6-12 months; group 3, 1-3 years; and group 4, > 3 years. Significant improvements were detected in 5 parameters (APVR, APAR, APWR1, rAPDR30, and lAPDR30) over time, whereas no significant differences were found in FA30, APWR2, rAPDR60, and lAPDR60 between age groups. CONCLUSIONS: Forehead shape (surface area and volume), as well as narrowing and anterolateral contour at the frontal points, differed significantly over time without surgery. However, forehead angulation, narrowing, and anterolateral contour at temporal points did not show significant differences. This knowledge will aid in surgical and parental decision-making.

Improved Facial and Skull-Base Symmetry following Osteotomy and Distraction of Unilateral Coronal Synostosis.

BACKGROUND: Unilateral coronal synostosis (UCS) results in a surgically demanding deformation, as the deformity is asymmetric in the calvaria but also presents with facial scoliosis and orbital dystopia. Traditional cranioplasties correct the forehead but have little effect on the face and orbits. In this article, the authors describe a consecutive series of patients operated on for UCS with osteotomy of the fused suture combined with distraction osteogenesis. METHODS: Fourteen patients (mean age, 8.0 months; range, 4.3 to 16.6 months) were included in this study. The authors measured and compared the orbital dystopia angle, anterior cranial fossa deviation, and anterior cranial fossa cant between preoperative computed tomography results and those at distractor removal. RESULTS: Blood loss was 6.1 mL/kg (range, 2.0 to 15.2 mL/kg), and length of stay was 4.4 days (range, 3.0 to 6.0 days). The authors observed significant improvements in the median orbital dystopia angle from 9.8 degrees (95% CI, 7.0 to 12.6 degrees) to 1.1 degrees (95% CI, -1.5 to 3.7 degrees) ( P < 0.001), anterior cranial fossa deviation from 12.9 degrees (95% CI, 9.2 to 16.6 degrees) to 4.7 degrees (95% CI, 1.5 to 7.9 degrees) ( P < 0.001), and anterior cranial fossa cant from 2.5 degrees (95% CI, 1.5 to 3.5 degrees) to 1.7 degrees (95% CI, 0.0 to 3.4 degrees) ( P = 0.003). CONCLUSIONS: Osteotomy combined with a distractor for UCS straightened the face and relieved orbital dystopia by affecting the nose angle relative to the orbits, correcting the deviation of the cranial base in the anterior fossa, and lowering the orbit on the affected side. Furthermore, this technique demonstrated a favorable morbidity profile with low perioperative bleeding and a short inpatient period, suggesting its potential to improve the surgical treatment of UCS. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Surgical Treatment of Trigonocephaly, Simplified Technique for Moderate Cases.

BACKGROUND: The prevalence of trigonocephaly has increased worldwide over the past 2 decades. Early identification and appropriate treatment are critical. The aim of this study is to evaluate the outcomes and the effect of metopic suture excision, perisutural frontal bone shave, and bilateral pericranial flap method on the shape of the forehead after surgical correction in infants with moderate trigonocephaly. METHODS: The present study was performed as a cross-sectional study on 40 infants of 3 to 12 months old with trigonocephalus who underwent metopic suture excision and pericardial flap surgery in Mofid Pediatric Hospital from 2016 to 2022. The definitive diagnosis of patients' trigonocephaly was made based on clinical signs and computed tomography scan findings by a plastic surgeon. RESULTS: Overall in 40 patients operated by this technique, 23 (57.5%) of cases were males, and 17 (42.5%) were females. The mean age of patients was 7.86 ± 2.22 months. Hospital stay was 2 to 4 days (mean: 3 d), intensive care unit admission was in 33 cases for 24 hours, and no intensive care unit admission for 7 cases. Blood was transfused during surgery for 25 patients, and 15 patients did not require blood transfusion use. Results were evaluated in 6 to 12 months after surgery by 3 independent plastic surgeons, with pre and postoperative photos. Satisfaction with the results of forehead shape was excellent for 60% of patients, good for 37.5%, and moderate for 2.5%. Only one female patient had a recurrence after the surgery. CONCLUSION: This study showed that the pericranial flap method after full metopic suture excision and frontal shave was very effective in the treatment of infants with moderate trigonocephaly.

Anatomical variations of the zygomaticofacial foramen and its related canal through the zygomatico-orbital and zygomaticotemporal foramina in dry human skulls.

PURPOSE: The aim of this study is to reveal the location of the zygomaticofacial foramina, the variations of their numbers, and their connections between the zygomatico-orbital and zygomaticotemporal foramina. METHODS: Ethics committee approval of our study was received by the Istanbul Medical Faculty Clinical Research Ethics Committee (date:30.07.2021, number:358356). 171 zygomatic bones of unknown gender from the Department of Anatomy, Istanbul University, were included in this study. The number of zygomaticofacial foramina and their connections with the zygomatico-orbital foramen and the zygomaticotemporal foramina were examined. Also, the morphometric distances between the zygomaticofacial foramen were calculated. Evaluation of the data was done with SPPS v.21. RESULTS: The number of zygomaticofacial foramina was found as 299. It was found single, double, three, four, five and six foramina, in 52 (30.4%), 52 (30.4%), 24 (14.03%), 10 (5.85%), 5 (2.93%), 1 (0.58%) zygomatic bone, respectively. Zygomaticofacial foramen was absent in 27 (15.8%) bones. Of these 299 foramina, 129 were found to be connected with zygomatico-orbital foramen and 23 with zygomaticotemporal foramen. It was noted that 147 zygomaticofacial foramina had no connection with any foramina. The distances between the zygomaticofacial foramen and the frontozygomatic suture, temporal process, maxillary process, the lowest point of the zygomatic bone, and orbital rim were found as 25.30 ± 2.81mm, 18.74 ± 3.56mm, 21.56 ± 4.16mm, 18.72 ± 2.57mm, 6.67 ± 3.27mm, respectively. CONCLUSION: Consequently, the location and variations of ZFF are of great importance for maxillofacial surgery and regional block anesthesia. Knowing its location and variations will help prevent complications during any surgical intervention in this region.

Midpalatal suture maturation in 15- to 35-year-olds: morphological assessment in the coronal plane using CBCT-an exploratory study.

Rapid maxillary expansion (RME) is used in patients presenting transverse maxillary deficiency. However, RME may be unpredictable after late adolescence if the midpalatal sutural maturation stage (MPMS) is in late stage. Since MPMS evaluation is influenced by the expertise of the operator and image quality, this classification method could be complemented. Therefore, this study aimed to analyze the morphology of the midpalatal suture (MPS) and its surrounding bone in the coronal plane using cone beam computed tomography (CBCT) images of adolescents and young adults and to correlate the findings with their respective MPMS status. CBCT scans of 200 patients aged 15-35 years of both sexes were evaluated. MPS and surrounding bone tissue characteristics in the coronal and axial sections were analyzed, and MPMS was evaluated (A to E). Six categories were identified for the coronal evaluation, analyzing it in 2 standardized locations. Sutural morphology: I, hypodense sutural line limited by 2 hyper-dense para-sutural lines; II, hypodense sutural line; and III, suture not visible. The presence of para-sutural cancellous bone: CB0, compact bone; CB1, dense cancellous tissue; CB2, spaced cancellous bone. Midpalatal bone thickness (MBTh) was also measured. ANOVA-Bonferroni, chi-square, logistic regression and t-tests were used. MPMS increased with age. Sutural morphology I and CB0 bone were the most prevalent. Here we show that sutural morphology, para-sutural bone characteristics, and MPSM were significantly associated. The coronal evaluation of the MPS can complement the information from the MPSM assessment, allowing the identification of patent MPS even in the presence of late MPSM.

Wormian Bones: Prevalence, Topography, and Implications.

BACKGROUND: Wormian bones also known as sutural bones are asymmetrical and shapeless bones occurring in cranial sutures and fontanelle of the skull. Their incidence is reported to vary in population. The exact etiology is debatable, but their formation is under the control of both genetic and environmental factors and has great anthropological and clinical implications related to the cranium. Due to high clinical relevance of Wormian bones, the study was carried out. The aim of the study is to expound the incidence and topography of Wormian bones along with clinical significance in dry adult skulls of Indian origin. METHODS: The study was conducted in the Department of Anatomy using 200 complete adult dry skulls of unknown age and sex. All the sutures in the skull were inspected for the presence of Wormian bones. The Wormian bones were classified into 10 categories, and associated implications were brought out. The Wormian bones were photographed, and details were compared with the available literature. RESULTS: The Wormian bones were observed in 190 (380 sides) skulls with 186 on the right side and 108 on the left side. The predominance site of sutural bone was lambdoid suture followed by sagittal suture. The least common site of Wormian bone was lambda. CONCLUSION: The detailed information of precise topography, frequency, and number of Wormian bones is of utmost use for surgeons performing surgery on the skull, anthropologists for identifying races, and forensic scientists for investigating child abuse cases.

Atypical sagittal suture craniosynostosis: pathological considerations for early closure of the anterior part of the sagittal suture.

Sagittal suture synostosis is one of the most common craniosynostoses and is often diagnosed by characteristic narrow and long skull shape, scaphocephaly. However, some patients with sagittal suture synostosis do not present with typical scaphocephaly, making early diagnosis difficult. In this study, five cases of characteristic skull deformity showing a narrowing of the cranium posterior to the coronal suture on computed tomography (CT) are presented. The three older children presented with papilledema and intellectual disability and a closed sagittal suture on CT. The two infant cases were diagnosed with the characteristic cranial deformities with aggravation of the deformity over time, but sagittal suture closure was not evident on CT. All patients underwent cranial remodeling surgery. In the two infant cases, the histopathological findings showed that the anterior part of the sagittal suture was firmly fused with fibrous tissue without bony fusion. These findings suggested that narrowing of the cranium posterior to the coronal suture might be due to functional fusion of the anterior portion of the sagittal suture prior to bony fusion. In an infant presenting with such a deformity that shows aggravation of the deformity over time, surgical treatment should be considered.

The Accuracy of Classification Systems in Nonsyndromic Sagittal Craniosynostosis.

Numerous classification systems of nonsyndromic sagittal craniosynostosis (NSC) are applied but none has gained a wide acceptance, since each classification is focused on distinct aspects. The aim of the study was to assess the accuracy of 4 classifications of NSC discussed in the literature by defining the associations among the classifications, individual features (sex, age, cranial index), and objective morphologic criteria (frontal bossing, retrocoronal constriction, sagittal ridge, and occipital bulleting). The study was conducted on anonymized thin-cut CT scans of 133 children with NSC 1 to 12 months old (mean age 5.42 mo). The type of cranial dysmorphology was assessed using 4 classification systems, focusing on skull shape, pattern of sagittal suture closure (Heuzé classification), deformation of skull vault (Sakamoto classification), and a single-dominant feature (David classification). Each patient was also independently investigated for the presence of morphologic criteria. A multivariate analysis was performed to explore the relations among the classifications and assess their accuracy. In the analyzed cohort sphenocephaly (38.3%), CFF type by Heuzé (30.8%), type I by Sakamoto (72.9%), and a central type by David (42.9%) were dominant findings. Regarding the morphologic criteria, frontal bossing was observed the most frequently (91.7%). The age of patients and cranial index differed significantly among the shapes of skull and David classifications ( P <0.001). The shape-based system showed the strongest correlation with other classifications and with measurable variables. Other classifications have much in common and some overlap, but none of them constitutes a standalone system to define all aspects of cranial dysmorphology in NSC.

Concurrent impact of de novo mutations on cranial and cortical development in nonsyndromic craniosynostosis.

OBJECTIVE: Nonsyndromic craniosynostosis (nsCS), characterized by premature cranial suture fusion, is considered a primary skull disorder in which impact on neurodevelopment, if present, results from the mechanical hindrance of brain growth. Despite surgical repair of the cranial defect, neurocognitive deficits persist in nearly half of affected children. Therefore, the authors performed a functional genomics analysis of nsCS to determine when, where, and in what cell types nsCS-associated genes converge during development. METHODS: The authors integrated whole-exome sequencing data from 291 nsCS proband-parent trios with 29,803 single-cell transcriptomes of the prenatal and postnatal neurocranial complex to inform when, where, and in what cell types nsCS-mutated genes might exert their pathophysiological effects. RESULTS: The authors found that nsCS-mutated genes converged in cranial osteoprogenitors and pial fibroblasts and their transcriptional networks that regulate both skull ossification and cerebral neurogenesis. Nonsyndromic CS-mutated genes also converged in inhibitory neurons and gene coexpression modules that overlapped with autism and other developmental disorders. Ligand-receptor cell-cell communication analysis uncovered crosstalk between suture osteoblasts and neurons via the nsCS-associated BMP, FGF, and noncanonical WNT signaling pathways. CONCLUSIONS: These data implicate a concurrent impact of nsCS-associated de novo mutations on cranial morphogenesis and cortical development via cell- and non-cell-autonomous mechanisms in a developmental nexus of fetal osteoblasts, pial fibroblasts, and neurons. These results suggest that neurodevelopmental outcomes in nsCS patients may be driven more by mutational status than surgical technique.