Cranial Base Width Research Articles

PRICKLE1 × FOCAD Interaction Revealed by Genome-Wide vQTL Analysis of Human Facial Traits.

The human face is a highly complex and variable structure resulting from the intricate coordination of numerous genetic and non-genetic factors. Hundreds of genomic loci impacting quantitative facial features have been identified. While these associations have been shown to influence morphology by altering the mean size and shape of facial measures, their effect on trait variance remains unclear. We conducted a genome-wide association analysis for the variance of 20 quantitative facial measurements in 2,447 European individuals and identified several suggestive variance quantitative trait loci (vQTLs). These vQTLs guided us to conduct an efficient search for gene-by-gene (G × G) interactions, which uncovered an interaction between PRICKLE1 and FOCAD affecting cranial base width. We replicated this G × G interaction signal at the locus level in an additional 5,128 Korean individuals. We used the hypomorphic Prickle1Beetlejuice (Prickle1Bj) mouse line to directly test the function of Prickle1 on the cranial base and observed wider cranial bases in Prickle1Bj/Bj. Importantly, we observed that the Prickle1 and Focadhesin proteins co-localize in murine cranial base chondrocytes, and this co-localization is abnormal in the Prickle1Bj/Bj mutants. Taken together, our findings uncovered a novel G × G interaction effect in humans with strong support from both epidemiological and molecular studies. These results highlight the potential of studying measures of phenotypic variability in gene mapping studies of facial morphology.

Long-Term Evaluation of Mandibular Growth in Children With FGFR2 Mutations.

Understanding mandibular growth in children with fibroblast growth factor receptor 2 (FGFR2) mutations is important for planning the degree of midface advancement, and for determining the best treatment for obstructive sleep apnea. Yet, relatively little is known about growth of the unoperated mandible in affected children. The purpose of this study was to evaluate mandibular growth through skeletal maturity in Apert, Crouzon, and Pfeiffer syndromes. A retrospective chart review was performed. Long-term, unoperated mandibular growth was assessed using multiple anthropologic measurements including: mandibular width, height, depth, and the cranial base width (approximating bicondylar width). Measurements were compared over 3 age intervals: 6 to 7 years, 10 years, and at skeletal maturity (15 years+). Out of 327 treated patients with FGFR2 mutations, 21 were found to have complete mandibular measurements through skeletal maturity (11 Apert, 7 Crouzon, and 3 Pfeiffer). Initial measurements revealed that mandibular height and bigonial breadth were slightly larger than normal, but sagittal depth and cranial base width were deficient. Early growth was slightly accelerated along the vertical and sagittal axes, stable across the bigonial distance, and marked deficient at the cranial base. At skeletal maturity, vertical height and bigonial width remained above average, but mandibular depth (forward sagittal growth) and cranial base width, remained deficient. Mandibular growth in children with FGFR2 mutations is not normal with impairments found in forward sagittal growth and skull base widening. Knowledge of these deficiencies has significant implications for both planning the degree of midfacial advancements, as well as treating obstructive sleep apnea.

Genome-Wide Association Study Reveals Multiple Loci Influencing Normal Human Facial Morphology.

Numerous lines of evidence point to a genetic basis for facial morphology in humans, yet little is known about how specific genetic variants relate to the phenotypic expression of many common facial features. We conducted genome-wide association meta-analyses of 20 quantitative facial measurements derived from the 3D surface images of 3118 healthy individuals of European ancestry belonging to two US cohorts. Analyses were performed on just under one million genotyped SNPs (Illumina OmniExpress+Exome v1.2 array) imputed to the 1000 Genomes reference panel (Phase 3). We observed genome-wide significant associations (p < 5 x 10−8) for cranial base width at 14q21.1 and 20q12, intercanthal width at 1p13.3 and Xq13.2, nasal width at 20p11.22, nasal ala length at 14q11.2, and upper facial depth at 11q22.1. Several genes in the associated regions are known to play roles in craniofacial development or in syndromes affecting the face: MAFB, PAX9, MIPOL1, ALX3, HDAC8, and PAX1. We also tested genotype-phenotype associations reported in two previous genome-wide studies and found evidence of replication for nasal ala length and SNPs in CACNA2D3 and PRDM16. These results provide further evidence that common variants in regions harboring genes of known craniofacial function contribute to normal variation in human facial features. Improved understanding of the genes associated with facial morphology in healthy individuals can provide insights into the pathways and mechanisms controlling normal and abnormal facial morphogenesis.

Anthropometric and craniofacial sexual dimorphism in obstructive sleep apnea patients: is there male-female phenotypical convergence?

Obstructive sleep apnea (OSA) is more common in men than women. Body size is greater in males (sexual dimorphism), but large body habitus is associated with OSA for both genders. We speculated that male-female phenotypical convergence (reduced sexual dimorphism via identical phenotype acquisition) occurs with OSA and tested hypotheses: (1) phenotypical features pathogenic for OSA differ between OSA and healthy subjects irrespective of gender; and (2) such characteristics exhibit phenotypical convergence. Utilizing an existing database, we calculated male-female (group average) ratios for eight anthropometric and 33 surface cephalometric variables from 104 Caucasian OSA patients [72 males; apnea-hypopnea index (events h(-1) ): males: 42.3 ± 24.7 versus females: 42.6 ± 26.1 (P > 0.9)] and 85 Caucasian, healthy, non-OSA, community volunteers (36 males). Log-transformed data were analysed using a general linear model with post-hoc unpaired t-tests and significance at P < 0.0012 (Bonferroni multiple-comparison correction). OSA patients were older (56.9 ± 14.4 versus 38.0 ± 13.8 years), but there were no within-group gender-based age differences. All anthropometric variables (except height), plus cranial base width, mandibular breadth and retromandibular width diagonal were larger in gender-matched OSA versus healthy comparisons; thus satisfying hypothesis (1). Male-female ratios were mostly >1.0 across groups, but with no significant group × gender interactions no variable satisfied hypothesis (2). Thus, in this exploratory study, OSA patients had gender-common phenotypical differences to healthy subjects, but sexual dimorphism was preserved. Lack of complete phenotypical convergence may indicate gender-based critical phenotype-level attainment for OSA and/or gender-based OSA prevalence arises from factors other than those in this study.

3D stereophotogrammetric analysis of operative effects after broad median craniectomy in premature sagittal craniosynostosis

There is ongoing discussion on the diagnostic methods, the need of surgical treatment, and the surgical strategies for premature craniosynostosis. This study examined the operative procedure of a standardized broad median craniectomy, active tilting of the forehead, and bitemporal greenstick fracturing in children with premature sagittal craniosynostosis. To objectively analyze the direct surgical results, we used a 3D stereophotogrammetry scanner, as previously described. A 3D analysis showed a significant increase in the width, cranial index (CI), head and coronal circumferences, intracranial volume, and cranial base width after surgery. Head length was the only parameter that demonstrated a significant decrease postoperatively. Asymmetry and the 30° diagonal difference showed no significant changes. 3D stereophotogrammetry is a reliable and valuable tool with no side effects. It demonstrated that the extended surgical procedure achieves good postoperative results with a reduced length and increased width and, therefore, an improved CI. Additionally, the total intracranial volume was significantly increased after surgery.

Morphological and morphometric study on sphenoid and basioccipital ossification in normal human fetuses

Congenital anomalies of the brain frequently correspond to cranial base anomalies, and a detailed description of morphology and individual variations in the developing cranial base is of clinical importance for diagnosing anomalies. Development of the human cranial base has been studied using dissection, computed tomography, and magnetic resonance imaging, each of which has advantages and disadvantages. We here examined development of the normal human fetal cranial base using bone staining, which allows for direct observation of the ossification centers and precise three-dimensional measurements. We observed alizarin red S-stained sphenoids and basiocciputs of 22 normal formalin-fixed human fetuses with crown-rump lengths (CRL) of 115-175 mm. We defined landmarks and measured sphenoids and basiocciputs using a fine caliper. Growth patterns of these ossifying bones were obtained, and we found similarities and differences among the growth patterns. We also observed individual variations in the ossification patterns, in particular, single- or double-ossification center patterns for the basisphenoid. The orbitosphenoid and basisphenoid widths and ratios of the widths to the total cranial base width were significantly different between the two pattern groups, whereas the other measurements and their ratios to the total cranial base did not differ between the groups. We measured the cerebrum and pons in different sets of 22 human fetuses with CRLs of 105-186 mm and found close relationships with the development of corresponding parts of the cranial base. The results contribute to the quantitative and qualitative information about the growth patterns and variations during human fetal cranial base development.

Three‐dimensional morphometric analysis of craniofacial shape in the unaffected relatives of individuals with nonsyndromic orofacial clefts: A possible marker for genetic susceptibility

Numerous studies have described altered patterns of craniofacial form in the unaffected relatives of individuals with nonsyndromic clefts. Unfortunately, results from such studies have been highly variable and have failed to provide a reliable method for differentiating "at-risk" relatives from controls. In the present study, we compared craniofacial shape between a sample of unaffected relatives (33 females; 14 males) from cleft multiplex families and an equal number of age/sex/ethnicity-matched controls. Sixteen x,y,z facial landmark coordinates derived from 3D photogrammetry were analyzed via Euclidean Distance Matrix Analysis, while 14 additional linear distances were analyzed via t tests. A subset of variables was then entered into a discriminant function analysis (DFA). Compared to controls, female unaffected relatives demonstrated increased upper facial width, midface reduction and lateral displacement of the alar cartilage. DFA correctly classified 70% of female unaffected relatives and 73% of female controls. Male unaffected relatives demonstrated increased upper facial and cranial base width, increased lower facial height and decreased upper facial height compared with controls. DFA correctly classified 86% of male unaffected relatives and 93% of male controls. In both sexes, upper facial width contributed most to group discrimination. Following DFA, unaffected relatives were assigned to risk/liability classes based on the degree of phenotypic divergence from controls. Results indicate that craniofacial shape differences characterizing unaffected relatives are partly sex-specific and are in broad agreement with previous reports. These findings further suggest that a quantitative assessment of the craniofacial phenotype may allow for the identification of susceptible individuals within nonsyndromic cleft families.

Cranial base influence on the nasomaxillary complex in Class II division 1 malocclusion (Three dimensional cephalometric study)

Aim: To evaluate the effect of the cranial base on the nasomaxillary complex in class II division 1 malocclusion. Materials and Methods: The study was carried out on a sample of 104 Iraqi subjects in Mosul City aged 18–24 years 53 females and 51 males having class II division 1 malocclusion. Lateral and posteroanterior radiographs were taken for each subject and twenty three measurements were used (Nine angular and fourteen linear). Results of the analysis were the median (NSBa), lateral cranial base (NSCo) and saddle angle (NSAr) showed a significant effect on the inclination of the Frankfort plane from the anterior and posterior cranial base in same direction, For the saddle angle significantly affect the inclination of the Frankfort plane but in the opposite direction while on anteroposterior position of alveolar process of the premaxilla (SNPr) in the same direction. The anterior part (SN), second lateral posterior part (SCo) and depth of cranial base (NBa) significantly affect the maxillary length (ApMax–PNS), upper anterior (N–ANS) and posterior facial height (S–PNS). For the median posterior part (SBa) and first lateral posterior part (SAr) no significant effect on (upper anterior facial height). The anterior cranial base width (GL–GL) showed a significant affect [facial (Zy–Zy), maxillary (J–J) and upper intermolar width (U6–U6)]. While posterior cranial base width (Mas–Mas) was significantly affect [facial (Zy–Zy), maxillary (J–J) and nasal width (Nc–Nc)].Conclusion: The median, lateral cranial base and saddle angles showed correlation with the inclination of the Frankfort plane from the anterior and posterior cranial base. The observed impact of the cranial base widths on the nasomaxillary complex widths were for anterior cranial base width there was a significant effect on bizygomatic, bimaxillary and intermolar width

Cranial Base in Newborns with Complete Cleft Lip and Palate: Radiographic Study

In a 1993 study, Mølsted and colleagues found an increased width of the spheno-occipital synchondrosis in newborns with complete clefts of the lip, alveolus, and palate compared with newborns with incomplete clefts. As the spheno-occipital synchondrosis represents remnants of the early chondrocranium that later ossifies and incorporates in the cranial base, it is possible that an inborn alteration, such as a deviant growth of cartilage, or a delayed maturation in the early development of the cartilaginous cranial base, can affect not only the length and the width of the cranial base, but also the petrous portion of the temporal bone and the nasal septum, as these structures also have a cartilaginous origin. The purpose of the present study was to measure the cranial base width, including the width of the maxilla, and to measure the bilateral angulation of the petrous portion of the temporal bone and the sphenoid bone in 3-month-old children with complete clefts and in 3-month-old children with an incomplete cleft of the lip, and to compare the two groups. Fifty-two children with complete clefts (CLP) without associated malformations comprised the test group. Forty-eight children with a minor, incomplete cleft lip (CL) constituted the control group. The results of the comparison showed marked differences between the CLP and CL groups. In the CLP children, the cranial base width and the bilateral angulation of the sphenoid bone increased. An increased angulation was also seen between left and right sides of the pars petrosa. Furthermore, increased maxillary width was found.(ABSTRACT TRUNCATED AT 250 WORDS)

Cranial Base in Newborns with Complete Cleft Lip and Palate: Radiographic Study

In a 1993 study, Mølsted and colleagues found an increased width of the spheno-occipital synchondrosis in newborns with complete clefts of the lip, alveolus, and palate compared with newborns with incomplete clefts. As the spheno-occipital synchondrosis represents remnants of the early chondrocranium that later ossifies and incorporates in the cranial base, it is possible that an inborn alteration, such as a deviant growth of cartilage, or a delayed maturation in the early development of the cartilaginous cranial base, can affect not only the length and the width of the cranial base, but also the petrous portion of the temporal bone and the nasal septum, as these structures also have a cartilaginous origin. The purpose of the present study was to measure the cranial base width, including the width of the maxilla, and to measure the bilateral angulation of the petrous portion of the temporal bone and the sphenoid bone in 3-month-old children with complete clefts and in 3-month-old children with an incomplete cleft of the lip, and to compare the two groups. Fifty-two children with complete clefts (CLP) without associated malformations comprised the test group. Forty-eight children with a minor, incomplete cleft lip (CL) constituted the control group. The results of the comparison showed marked differences between the CLP and CL groups. In the CLP children, the cranial base width and the bilateral angulation of the sphenoid bone increased. An increased angulation was also seen between left and right sides of the pars petrosa. Furthermore, increased maxillary width was found.(ABSTRACT TRUNCATED AT 250 WORDS)

The human chin and its relationship to mandibular morphology.

This study evaluated the proportion of the external chin (protuberantia mentalia) in relation to the total symphyseal area in normal jaws and those with a diverse morphology. A sample of 60 cases was randomly selected and divided into three groups of 20 each on the basis of normal growth, horizontal growth and vertical growth with an open bite. Tracings of lateral dn frontal radiographs were used to describe general mandibular form and to determine the percentage of external/total symphyseal area. Dental casts were also examined to determine a basal arch form ratio. The results of this study indicate that the amount of bony chin present is related to certain morphologic features of the mandible. The most significant findings illustrate: 1. The chin increases in size as the mandibular type varies from a vertical type, to a normal type, to a horizontal type of growth pattern. 2. With dental "hypofunction" in combination with an exaggerated vertical development of the mandible, a smaller proportion of the protruding chin is present. 3. The chin increases in size as the mandibular basal arch form varies from a tapered shape for the vertical cases to a more square form in the horizontal cases. 4. The degree of lateral ramal flair does not appear to influence the proportion of protruding chin present. Several models have been presented which attempt to explain protuberantia mentalia variation. The evidence in this study supports the concept that mandibular morphology is the result of the action of compensative adaption in a developing structure. There appears to be an implied polygenic influence on symphyseal morphology operating from the cartilaginous cranial base and mandibular basilar bone. This may be manifested in the relative proportion of mandibular basal bone to cranial base width, and to the vector of cranial base growth. The ultimate proportion of the bony chin is viewed to be the result of mandibular adaption to a functional musculoskeletal balance in the craniofacial complex. The extreme variability of chin form in man may be considered to be the result of compensative growth developing in response to the most structurally efficient jaw form, the contiguous soft and hard tissue environment, and the intrinsic genotype of the mandible.

Birotundal diameter of the human sphenoid bone from age six years to early adulthood.

AbstractLongitudinal data for a twenty‐year period are presented for a dimension of the human sphenoid bone as seen on postero‐anterior roentgenograms of 22 males and 18 females (healthy, American‐born Caucasoids). Birotundal diameter measured as the distance between the centers of the right and left foramen rotundum averaged near 32.0 mm for each sex at age 6 years. Individual increase in size to age 26 years ranged between 3.2 mm and 8.3 mm. There is no correlation between size at age 6 years and change between this age and early adulthood.For 54 males and 50 females at age 9 years, intercorrelations were obtained among six variables: birotundal diameter, head breadth, bizygomatic diameter, bigonial diameter, upper and loweer dental arch widths at the permanent first molars. The r's were nonsignificant or low positive (with the exception of upper‐lower dental arch, r = 0.76).The results of this study are aligned with three previous studies of human cranial base width.