Physiologic Timeline of Cranial-Base Suture and Synchondrosis Closure.

BACKGROUND: Fusion of cranial-base sutures/synchondroses presents a clinical conundrum, given their often unclear "normal" timing of closure. This study investigates the physiologic fusion timelines of cranial-base sutures/synchondroses. METHODS: Twenty-three age intervals were analyzed in subjects aged 0 to 18 years. For each age interval, 10 head computed tomographic scans of healthy subjects were assessed. Thirteen cranial-base sutures/synchondroses were evaluated for patency. Partial closure in greater than or equal to 50 percent of subjects and complete bilateral closure in less than 50 percent of subjects defined the fusion "midpoint." Factor analysis identified clusters of related fusion patterns. RESULTS: Two hundred thirty scans met inclusion criteria. The sutures' fusion midpoints and completion ages, respectively, were as follows: frontoethmoidal, 0 to 2 months and 4 years; frontosphenoidal, 6 to 8 months and 12 years; and sphenoparietal, 6 to 8 months and 4 years. Sphenosquamosal, sphenopetrosal, parietosquamosal, and parietomastoid sutures reached the midpoint at 6 to 8 months, 8 years, 9 to 11 months, and 12 years, respectively, but rarely completed fusion. The occipitomastoid suture partially closed in less than or equal to 30 percent of subjects. The synchondroses' fusion midpoints and completion ages, respectively, were as follows: sphenoethmoidal, 3 to 5 months and 5 years; spheno-occipital, 9 years and 17 years; anterior intraoccipital, 4 years and 10 years; and posterior intraoccipital, 18 to 23 months and 4 years. The petro-occipital synchondrosis reached the midpoint at 11 years and completely fused in less than 50 percent of subjects. Order of fusion of the sutures, but not the synchondroses, followed the anterior-to-posterior direction. Factor analysis suggested three separate fusion patterns. CONCLUSIONS: The fusion timelines of cranial-base sutures/synchondroses may help providers interpret computed tomographic data of patients with head-shape abnormalities. Future work should elucidate the mechanisms and sequelae of cranial-base suture fusion that deviates from normal timelines.

Respective Roles of Craniosynostosis and Syndromic Influences on Cranial Fossa Development.

BACKGROUND: Little is known about the detailed growth of the cranial fossae, even though they provide an important structural connection between the cranial vault and the facial skeleton. This study details the morphologic development of isolated cranial vault synostosis and associated syndromes on cranial fossa development. METHODS: A total of 125 computed tomographic scans were included (nonsyndromic bicoronal synostosis, n = 36; Apert syndrome associated with bicoronal synostosis, n = 24; Crouzon syndrome associated with bicoronal synostosis, n = 11; and controls, n = 54). Three-dimensional analyses were produced using Materialise software. RESULTS: The regional anterior and middle cranial fossae volumes of nonsyndromic bicoronal synostosis are characterized by significant increases of 43 percent (p < 0.001) and 60 percent (p < 0.001), respectively, and normal posterior cranial fossa volume. The cranial fossae depths of nonsyndromic bicoronal synostosis were increased, by 37, 42, and 21 percent (all p < 0.001) for anterior, middle, and posterior cranial fossae, respectively, accompanying the shortened cranial fossae lengths. The volume and morphology of all cranial fossae in Apert syndrome nearly paralleled nonsyndromic bicoronal synostosis. However, Crouzon syndrome had reduced depths of cranial fossae, and more restricted fossa volumes than both Apert syndrome and nonsyndromic bicoronal synostosis. CONCLUSIONS: Cranial vault suture synostosis is likely to be more influential on cranial fossae development than other associated influences (genetic, morphologic) in Apert and Crouzon syndromes. Isolated Apert syndrome pathogenesis is associated with an elongation of the anterior cranial fossa length in infants, whereas in Crouzon syndrome, there is a tendency to reduce cranial fossa depth, suggesting individual adaptability in cranial fossae development related to vault synostosis.

The Influence of Lip Repair on the Growth of Craniofacial Structures in Bilateral Cleft Lip and Palate Patients With Unoperated Palate From Childhood to Adulthood.

PURPOSE: Surgical treatment of complete bilateral cleft lip and palate (BCLP) is the most difficult procedure among common cleft lip and palate. This study was to research the long-term effect of lip surgery by localizing the craniofacial growth pattern of BCLP patients in the Han people in western China compared with normal healthy people from childhood to adulthood. PATIENTS AND METHODS: A cross-sectional study included a sample of 43 BCLP patients who have received lip repair and a control group of 55 normal healthy people with Angle Class I occlusion at the similar age, gender and ethnicity, and all participants were obtained from the Department of Oral and Maxillofacial Surgery, Sichuan University. Sixteen linear and 14 angular bony landmarks were identified on lateral cephalometric radiographs at the average age of 5.6-year-old, 10.7-year-old, and 24.2-year-old. The measurements were used to represent the growth changes of cranial base, bony nasopharynx, maxillary, mandibular and maxilla-mandibular relationship. Between-group differences were assessed by using the Independent-Sample t test. RESULT: Lip repair has a slow and long-term effect on the craniofacial morphology. The tension from repaired orbicularis oris muscle would cause a decrease in maxillary sagittal length and the retroposition of maxilla combined with the mandibular functional displacement, which would cause a positive change in the postoperative facial morphology of BCLP patients in the long run. CONCLUSION: BCLP patients who have undergone lip repair at an early age have the potential to develop better facial convexity.

Cranial Fossa Volume and Morphology Development in Apert Syndrome.

BACKGROUND: Apert syndrome causes normal or enlarged intracranial volume overall as patients grow. This study aimed to trace the segmental anterior, middle, and posterior cranial fossae volume and structural morphology in these patients, to help discern a more focused and individualized surgical treatment plan for patients with Apert syndrome. METHODS: This study included 82 preoperative computed tomographic scans (Apert, n = 32; control, n = 50) divided into five age-related subgroups. The scans were measured using image processing and three-dimensional modeling software. RESULTS: The middle cranial fossa volume was increased and was the earliest change noted. It was increased by 45 percent (p = 0.023) compared with controls before 6 months of age and remained increased into adulthood (161 percent, p = 0.016), with gradually increasing severity. The anterior and posterior cranial fossae volumes also increased, by 35 percent (p = 0.032) and 39 percent (p = 0.007), respectively. Increased depth of cranial fossae contributed most to the increase in volumes of patients with Apert syndrome, with correlation coefficients of 0.799, 0.908, and 0.888 for anterior, middle, and posterior cranial fossa, respectively. The intracranial volume was increased 12 percent (p = 0.098) across the entire test age range (0 to 26 years old), but only had statistical significance during the age range of 6 to 18 years (22 percent, p = 0.001). CONCLUSIONS: Malformation of the middle cranial fossa is an early, perhaps the initial, pivotal cranial morphologic change in Apert syndrome. Increased cranial fossae depth is an inherent characteristic of the maldevelopment. Normalization of cranial volume and circumference overall may not achieve a normal skull structure, as it does not correct regional craniocerebral disproportion.

CBCT assessment of posterior cranial base and surrounding structures in orthodontically treated adolescents.

OBJECTIVE: Understanding craniofacial growth and development is important for accurate diagnosis, treatment planning and post-treatment evaluation of orthodontic cases. Paramount to this is knowledge of the cranial base growth and development, since it is the foundation upon which the remaining facial structures develop. The purpose of this study was to analyse different anatomical structures in the posterior cranial base and determine its changes during the adolescent years (13-15 year of age) using CBCT. MATERIALS AND METHODS: Sixty CBCT images of the adolescent population that received orthodontic treatment at two time-points (mean age T1: 13.1 years/T2: 14.6years) were used to assess growth related dimensional changes using 33 selected landmarks. Inter-rater, intra-rater and accuracy of 33 selected landmarks in the posterior cranial base and surrounding area were then evaluated via three-dimensional (3D) cone-beam computed tomography (CBCT). Linear differences were then calculated among the different landmarks to determine the changes present in the sample. RESULTS: The selected landmarks in the posterior cranial base and surrounding area were found to be reliably and accurately located in 3D. Over the growth period studied (17.5months), minor statistically significant changes occurred, but they were deemed clinically irrelevant. CONCLUSIONS: The studied landmarks in the posterior cranial base and surrounding area showed minor clinically insignificant changes over the study period. The observed changes could be attributed to measurement error. The posterior cranial base is deemed to be stable in all three dimensions of study during the adolescent growth period studied.

[Development and growth of the skull base]. / Développement et croissance de la base du crâne.

The skull base is a part of the neuro-cranium formed by endochondral ossification. The embryological origin of the skull base is not perfectly known, but there seems to be an anterior region derived from the neural crest and a posterior part derived from the mesoderm. Further studies are needed to define reliable presumptive maps. The origin of the different components of the occipital bone is just as poorly known. Much fundamental work remains to be done to suggest any solution to these problems in humans.

Basicranial ontogeny comparison in Pan troglodytes and Homo sapiens and its use for developmental stage definition of KNM-ER 42700.

OBJECTIVE: This study aims to develop a comparative basis for assessing the developmental stage of KNM-ER 42700 based on the ontogenetic pattern of the ectocranial surface of the basicranium in modern humans and chimpanzees. MATERIALS AND METHODS: A total of 33 landmarks were collected from an ontogenetic sample of modern humans (80), chimpanzees (51), and 12 individuals classified as Homo erectus s.l. Ontogenetic trajectories were analyzed, and common aspects were extracted for the purpose of discriminating age groups. A regression of size on the extracted shape variables was used to investigate common ontogenetic allometry. RESULTS: The basicranial development of chimpanzees and humans follows different trajectories; however, similarities are also present. The common shape component of development extracted can be used to define age groups in both chimpanzees and modern humans. The extracted shape component presents a similar ontogenetic and static-allometric pattern in these two species. The developmental stages of H. erectus s.l. specimens were attributed following these common traits. Our analysis correctly assigned developmental stages to those specimens of H. erectus for which developmental ages are known. DISCUSSION: The component used for assessing the developmental stage has an ontogenetic allometric component. However, this shape component can discriminate age group irrespective of size and is no longer related to size when static allometry is considered. Adult H. erectus s.l. specimens were attributed to the adult category. KNM-WT 15000 fell with the late juvenile age group, whereas D2700 plotted in the region of overlap between the juvenile and adult age groups and Mojokerto with the younger age groups, as predicted by their known developmental ages. KNM-ER 42700 fell within the adult variability despite its incompletely fused spheno-occipital synchondrosis.

Stem cells of the suture mesenchyme in craniofacial bone development, repair and regeneration.

Development of the skeleton is mediated through two distinct ossification mechanisms. Craniofacial bones are formed mainly through intramembranous ossification, a mechanism different from endochondral ossification required for development of the body skeleton. The skeletal structures are quite distinct between the two, thus they are likely to have their unique stem cell populations. The sutures serve as the growth center critical for healthy development of the craniofacial skeleton. Defects in suture morphogenesis cause its premature closure, resulting in development of craniosynostosis, a devastating disease affecting 1 in ~2,500 individuals. The suture mesenchyme has been postulated to act as the niche of skeletal stem cells essential for calvarial morphogenesis. However, very limited knowledge is available for suture biology and suture stem cells (SuSCs) have yet to be isolated. Here we report the first evidence for identification and isolation of a stem cell population residing in the suture midline. Genetic labeling of SuSCs shows their ability to self-renew and continually give rise to mature cell types over a 1-year monitoring period. They maintain their localization in the niches constantly produce skeletogenic descendants during calvarial development and homeostastic maintenance. Upon injury, SuSCs expand drastically surrounding the skeletogenic mesenchyme, migrate to the damaged site and contribute directly to skeletal repair in a cell autonomous fashion. The regeneration, pluripotency and frequency of SuSCs are also determined using limiting dilution transplantation. In vivo clonal expansion analysis demonstrates a single SuSC capable of generating bones. Furthermore, SuSC transplantation into injured calvaria facilitates the healing processes through direct engraftments. Our findings demonstrate SuSCs are bona fide skeletal stem cells ideally suited for cell-based craniofacial bone therapy as they possess abilities to engraft, differentiate.(Presented at the 1980th Meeting, April 16, 2019).

Intracranial Venous Hypertension in Craniosynostosis: Mechanistic Underpinnings and Therapeutic Implications.

Patients with complex, multisutural, and syndromic craniosynostosis (CSO) frequently exhibit intracranial hypertension. The intracranial hypertension cannot be entirely attributed to the craniocephalic disproportion with calvarial restriction because cranial vault expansion has not consistently alleviated elevated intracranial pressure. Evidence has most strongly supported a multifactorial interaction, including venous hypertension along with other pathogenic processes. Patients with CSO exhibit marked venous anomalies, including stenosis of the jugular-sigmoid complex, transverse sinuses, and extensive transosseous venous collaterals. These abnormal intracranial-extracranial occipital venous collaterals might represent anomalous development, with persistence and subsequent enlargement of channels normally present in the fetus, either as a primary defect or as nonregression in response to failure of the development of the jugular-sigmoid complexes. It has been suggested by some investigators that venous hypertension in patients with CSO could be treated directly via jugular foraminoplasty, venous stenting, or jugular venous bypass, although these options are not in common clinical practice. Obstructive sleep apnea, occurring as a consequence of midface hypoplasia, can also contribute to intracranial hypertension in patients with syndromic CSO. Thus, correction of facial deformities, as well as posterior fossa decompression, could also play important roles in the treatment of intracranial hypertension. Determining the precise mechanistic underpinnings underlying intracranial hypertension in any given patient with CSO requires individualized evaluation and management.

Covariation of the endocranium and splanchnocranium during great ape ontogeny.

That great ape endocranial shape development persists into adolescence indicates that the splanchnocranium succeeds brain growth in driving endocranial development. However, the extent of this splanchnocranial influence is unknown. We applied two-block partial least squares analyses of Procrustes shape variables on an ontogenetic series of great ape crania to explore the covariation of the endocranium (the internal braincase) and splanchnocranium (face, or viscerocranium). We hypothesized that a transition between brain growth and splanchnocranial development in the establishment of final endocranial form would be manifest as a change in the pattern of shape covariation between early and adolescent ontogeny. Our results revealed a strong pattern of covariation between endocranium and splanchnocranium, indicating that chimpanzees, gorillas, and orangutans share a common tempo and mode of morphological integration from the eruption of the deciduous dentition onwards to adulthood: a reflection of elongating endocranial shape and continuing splanchnocranial prognathism. Within this overarching pattern, we noted that species variation exists in magnitude and direction, and that the covariation between the splanchnocranium and endocranium is somewhat weaker in early infancy compared to successive age groups. When correcting our covariation analyses for allometry, we found that an ontogenetic signal remains, signifying that allometric variation alone is insufficient to account for all endocranial-splanchnocranial developmental integration. Finally, we assessed the influence of the cranial base, which acts as the interface between the face and endocranium, on the shape of the vault using thin-plate spline warping. We found that not all splanchnocranial shape changes during development are tightly integrated with endocranial shape. This suggests that while the developmental expansion of the brain is the main driver of endocranial shape during early ontogeny, endocranial development from infancy onwards is moulded by the splanchnocranium in conjunction with the neurocranium.

Early treatment of pseudo-class III malocclusion with modified swallowing occlusal contact intercept appliance (S.O.C.I.A.).

AIMS: The aim of the present work was to evaluate the dentoskeletal effects of swallowing occlusal contact intercept appliance (SOCIA) III in pseudo Class III malocclusion treatment. MATERIALS AND METHODS: Thirty-six patients (mean age: 9.46 years old) with pseudo-Class III malocclusion and 22 pseudo-Class III untreated controls (mean age: 8.7 years old) were selected and examined. All patients presented with a cervical stage CS2, CS3, or CS4. Patients with CS5 were not enrolled in the study. Cephalometric analysis was performed before phase 1 treatment (T1) and immediately following phase 2 treatment (T2). STATISTICAL ANALYSIS: Paired t-test and independent t-test. RESULTS: SOCIA III had skeletal and dental effects. The main effects of SOCIA III were on the midface with an effective increase of the sagittal growth (cranial base P < 0.001, anterior cranial base (ACB) P < 0.001, and maxilla growth P < 0.001) and vertical growth (anterior facial height P < 0.001). The effects of SOCIA on the mandible were a control of mandibular postrotation (P = 0.82) and the sagittal growth (P < 0.007). At the end of the treatment, a normal overjet was achieved (P < 0.001). CONCLUSIONS: The SOCIA III effects are resumed as follow: (a) an effective maxillary sagittal increase on the sagittal plane; (b) a vertical mandibular control; (c) a resolution of overjet; (d) no increase of overbite; (e) a stimulation of ACB growth.

Temporal Progression of Craniofacial Dysmorphology in Unilateral Coronal Synostosis: A Mechanistic Hypothesis.

AIM: This study chronicles skull base and face development in nonsyndromic unilateral coronal synostosis (UCS) during infancy, to characterize the mechanistic progression of facial dysmorphology. METHODS: Computed tomography scans from 51 subjects were reviewed (26 UCS, 25 controls) and data were reconstructed. Patients were stratified into 5 age groups. A series of measurements were taken from the reconstructions. RESULTS: All patients had a unilaterally fused coronal suture at the time of analysis. Asymmetry of the sphenoid wings was present across all age groups. The sphenoid wing ipsilateral to the fused suture consistently had a more acute angle from the midline. At 19 days of age, ipsilateral nasal root and cribriform plate deviation are noted, as well as increased contralateral zygoma antero-posterior length. Patients younger than 2 months also had elongated posterior cranial bases. At 2 to 3 months of age, the cranial base widens in the anterior portion of the middle cranial fossa with an increased ipsilateral pterion to sella distance. The most delayed change observed was the increase in contralateral orbital rim angle at 7 to 12 months of age compared to normal. CONCLUSION: After suture fusion, sphenoid wing changes are among the earliest restructural malformations to take place. This suggests that the cascade of dysmorphology in UCS originates in the cranial vault, then progresses to the skull base, and lastly to the facial structures. Ipsilateral orbital changes are early facial changes in UCS that begin before 2 months of age. This is then followed by changes in the contralateral face later in development.

Growth and Development of Craniofacial Structures in Patients at Different Ages With Unrepaired Submucous Cleft Palate.

PURPOSE: Submucous cleft palate (SMCP) is a particular subtype of cleft palate deformity; research related to the craniofacial features of patients with SMCP is comparatively rare. The study objective was to perform a cephalometric comparison of the craniofacial features of patients with SMCP and non-cleft controls at different ages. MATERIALS AND METHODS: The sample in this cross-sectional study was composed of 2 groups: SMCP patients and non-cleft controls. The primary predictor variables were study group (cleft and non-cleft) and age. Age was divided into 3 groups. The outcome variables of interest were craniofacial measurements. The measurements used reflect cranial length, cranial angle, maxillary sagittal length and protrusion, maxillary vertical height, pharyngeal depth, facial height, mandibular length and protrusion, mandibular plane angle, and intermaxillary relation. Adjusted cephalometric craniofacial measurements between the groups were compared in 3 age groups using generalized linear models after being adjusted for age and gender. RESULTS: The study included 60 SMCP patients and 60 non-cleft controls. SMCP patients and non-cleft controls were divided into 3 subgroups: those aged 5 to 7 years, those aged 9 to 11 years, and those aged 18 to 30 years. Patients with SMCP at age 5 to 7 years showed a shortened cranial base length, maxillary sagittal length and height, and bony pharynx depth. Patients with SMCP at age 9 to 11 years showed a smaller maxillary sagittal length and bony pharynx depth and an inharmonious jaw relationship. Patients with SMCP at age 18 to 30 years showed a smaller maxillary sagittal length and height and an inharmonious jaw relationship. CONCLUSIONS: SMCP is associated with progressive maxillary retrognathism and reduced profile convexity from childhood to adulthood.

Effects of Palate Repair on Cranial Base and Maxillary Morphology in Patients With Unilateral Complete Cleft Lip and Palate.

OBJECTIVE: To identify the effects of palate repair on cranial base and maxillary morphology in patients with unilateral cleft lip and palate (UCLP) and to discover the relevance between cranial base and maxilla through cephalometric analysis. DESIGN: Retrospective. PATIENTS: Thirty-seven UCLP patients with operated lip (OL) and unoperated palate constituted OL group and were classified into 5 cervical vertebral maturation (CVM) stages. Thirty-seven UCLP patients with operated lip and palate (OLP) and 37 noncleft people with skeletal class I malocclusion were CVM- and sex-matched with the OL group as OLP group and control group, respectively. CVM stage I and II were combined into group 1, CVM stage III to V were combined into group 2. INTERVENTIONS: Lateral cephalograms of all participants were obtained. MAIN OUTCOME MEASURES: Cephalometric analysis was employed, and data were compared among groups. RESULTS: Length of posterior cranial base (Ba-S) of the OL group was shorter than controls in group 1; Ba-S and the ratio between length of posterior and anterior cranial base (Ba-S/S-N) of the OL and OLP groups were smaller than controls in group 2. No significant differences in cranial base were found between the OL and OLP groups. In group 1, patients of the OLP group showed smaller SNA, ANS-Ptm, and ANS-Ptm/S-N, and patients of the OL group showed smaller ANS-Ptm. In group 2, both OL and OLP groups had smaller sella-nasion-A point angle (SNA), projection distance between ANS and Ptm points on FH plane (ANS-Ptm), and the ratio between ANS-Ptm and anterior cranial base length (ANS-Ptm/S-N). CONCLUSIONS: Palate repair seems to have no obvious effects on cranial base morphology in patients with UCLP. Those patients with lip operated, whether cleft palate operated or not, tend to have a smaller length of maxilla sagittally and this deformity progresses with age.

Ethnic differences in craniofacial and upper spine morphology in children with skeletal Class II malocclusion.

OBJECTIVES: To analyze differences in upper cervical spine and craniofacial morphology, including posterior cranial fossa and growth prediction signs, between Danish and South Korean pre-orthodontic skeletal Class II children and to analyze associations between upper cervical spine morphology and craniofacial characteristics. MATERIALS AND METHODS: One hundred forty-six skeletal Class II children-93 Danes (54 boys and 39 girls, mean age 12.2 years) and 53 Koreans (27 boys and 26 girls, mean age 10.8 years)-were included. Upper spine morphology, Atlas dimensions, and craniofacial morphology, including posterior cranial fossa and growth prediction signs, were assessed on lateral cephalograms. Differences and associations were analyzed by multiple linear and logistic regression analyses adjusted for age and gender. RESULTS: Significant differences between the ethnic groups were found in the sagittal and vertical craniofacial dimensions ( P < .001), mandibular shape ( P < .01), dental relationship ( P < .01), posterior cranial fossa ( P < .05), and growth prediction signs ( P < .001). No significant differences were found in upper spine morphology and Atlas dimensions between the groups. Upper spine morphology/dimensions were significantly associated with the cranial base angle ( P < .01), sagittal craniofacial dimensions ( P < .001), posterior cranial fossa ( P < .001), and growth prediction signs ( P < .05). CONCLUSIONS: Upper spine morphology/dimensions may be valuable as predictive factors in treatment planning for growing Class II children.

Transcription factor Foxc1 is involved in anterior part of cranial base formation.

The cranial base is a structure mainly formed through endochondral ossification and integrated into the craniofacial complex, which acts as an underlying platform for the developing brain. Foxc1 is an indispensable regulator during intramembranous and endochondral ossification. In this study, we found that the spontaneous loss of Foxc1 function in a mouse (congenital hydrocephalous), Foxc1ch/ch , demonstrated the anterior cranial base defects, including unossified presphenoid and lack of middle part of the basisphenoid bone. Hypoplastic presphenoid primordial cartilage (basal portion of the trabecular cartilage [bTB]) and a lack of the middle part of basisphenoid primordial cartilage (the hypophyseal cartilage) were consistently observed at earlier developmental stage. Foxc1 was expressed robustly and ubiquitously in undifferentiated mesenchyme of the cranial base-forming area in E11.0 wild-type fetuses. Once chondrogenesis commenced, the expression was downregulated and later limited to the perichondrium. Detection of transcripts of Collagen type2 A1 (Col2a1) revealed that both bTB and the anterior part of the hypophyseal cartilage developing anterior to the persistent epithelial stalk of the anterior lobe of the pituitary gland were suppressed in the Foxc1ch/ch . Proliferation activity of chondrocyte precursor cells was higher in the Foxc1ch/ch . Loss of Foxc1 function only in the neural crest cell lineage (Wnt1-cre;Foxc1ch/flox ) showed ossification of the posterior part of the hypophyseal cartilage derived from the mesoderm. These findings suggest that Foxc1 is an important regulator to further chondrogenesis and initiate the ossification of the presphenoid and basisphenoid bones.

Reduced Intercarotid Artery Distance in Syndromic and Isolated Brachycephaly.

INTRODUCTION: The morphology of the skull base can be altered in craniosynostoses. The objective of this study is to evaluate the reduced intercarotid artery distance in the lacerum segment in patients with syndromic and isolated brachycephaly. MATERIALS AND METHODS: The distances between the inner walls of the carotid canal at the lacerum segment were measured on high-resolution CT scans in children with Crouzon (25), Pfeiffer (21), Apert (26), Saethre-Chotzen (7) syndromes, isolated bicoronal synostosis (9), and compared to an age-matched control group (30). RESULTS: A significantly smaller mean distance between carotid canal walls was observed in Crouzon (11.1 ± 4.9 mm), Pfeiffer (9.6 ± 5.1 mm), Apert (12.3 ± 4.3 mm), Saethre-Chotzen (14.8 ± 3.0 mm) syndromes, and isolated bicoronal synostosis (14.9 ± 3.7 mm) as compared to the control group (19.7 ± 2.4 mm, P < 0.001, P < 0.001, P < 0.001, P = 0.005, and P = 0.002, respectively). There was no statistically significant difference in intercarotid canal distance among the Apert, Saethre-Chotzen and isolated bicoronal synostosis groups. Overall, the brachycephalic group showed reduced intercarotid canal distance comparing to controls (P < 0.001). DISCUSSION AND CONCLUSIONS: There is significant reduction of the distance between carotid canals in brachycephalic patients. This distance is more significantly altered in FGFR-related brachycephaly syndromes (especially Crouzon and Pfeiffer syndromes), than Saethre-Chotzen syndrome (TWIST1 mutation) and isolated non-syndromic bicoronal synostosis. This study highlights the importance of FGFRs in shaping the skull base. Altered vascular course of the internal carotid arteries can have important implications in planning skull base surgery in brachycephalic patients.

Posterior cranial base natural growth and development: A systematic review.

OBJECTIVE: To provide a synthesis of the published studies evaluating the natural growth and development of the human posterior cranial base (S-Ba). MATERIALS AND METHODS: The search was performed on MEDLINE, Embase, PubMed, and all EBM Reviews electronic databases. In addition, reference lists of the included studies were hand-searched. Articles were included if they analyzed posterior cranial-base growth in humans specifically. Study selection, data extraction, and risk of bias assessment were completed in duplicate. A meta-analysis was not justified. RESULTS: Finally, 23 published studies were selected: 5 cross-sectional and 18 cohort studies. Articles were published between 1955 and 2015, and all were published in English. The sample sizes varied between 20 and 397 individuals and consisted of craniofacial measurements from either living or deceased human skulls. Validity of the measurements was not determined in any of the studies, while six papers reported some form of reliability assessment. All the articles included multiple time points within the same population or data from multiple age groups. Growth of S-Ba was generally agreed to be from spheno-occipital synchondrosis growth. Basion displaced downward and backward and sella turcica moved downward and backward during craniofacial growth. Timing of cessation of S-Ba growth was not conclusive due to limited identified evidence. CONCLUSIONS: Current evidence suggests that S-Ba is not totally stable, as its dimensions change throughout craniofacial growth and a minor dimensional change is observed even in late adulthood.

Mouse models for the study of cranial base growth and anomalies.

The cranial base is a central and integral component of the cranioskeleton, yet little is known about its growth. Despite the dissimilarities between human and murine cranioskeletal form, mouse models are proving instrumental in studying craniofacial growth. The objectives of this review are to summarize recent findings from numerous mouse models that display growth defects in one or more cranial base synchondroses, with accompanying changes in chondrocyte cellular zones. Many of these models also display altered growth of the cranial vault and/or the facial region. FGFR, PTHrP, Ihh, BMP and Wnt/ß-catenin, as well as components of primary cilia, are the major genes and signalling pathways identified in cranial base synchondroses. Together, these models are helping to uncover specific genetic influences and signalling pathways operational at the cranial base synchondroses. Many of these genes are in common with those of importance in the cranial vault and the facial skeleton, emphasizing the molecular integration of growth between the cranial base and other cranial regions. Selected models are also being utilized in testing therapeutic agents to correct defective craniofacial and cranial base growth.

Thyroxine Exposure Effects on the Cranial Base.

Thyroid hormone is important for skull bone growth, which primarily occurs at the cranial sutures and synchondroses. Thyroid hormones regulate metabolism and act in all stages of cartilage and bone development and maintenance by interacting with growth hormone and regulating insulin-like growth factor. Aberrant thyroid hormone levels and exposure during development are exogenous factors that may exacerbate susceptibility to craniofacial abnormalities potentially through changes in growth at the synchondroses of the cranial base. To elucidate the direct effect of in utero therapeutic thyroxine exposure on the synchondroses in developing mice, we provided scaled doses of the thyroid replacement drug, levothyroxine, in drinking water to pregnant C57BL6 wild-type dams. The skulls of resulting pups were subjected to micro-computed tomography analysis revealing less bone volume relative to tissue volume in the synchondroses of mouse pups exposed in utero to levothyroxine. Histological assessment of the cranial base area indicated more active synchondroses as measured by metabolic factors including Igf1. The cranial base of the pups exposed to high levels of levothyroxine also contained more collagen fiber matrix and an increase in markers of bone formation. Such changes due to exposure to exogenous thyroid hormone may drive overall morphological changes. Thus, excess thyroid hormone exposure to the fetus during pregnancy may lead to altered craniofacial growth and increased risk of anomalies in offspring.