Age-related changes of the craniofacial skeleton: an anthropometric and histologic analysis.

With the development of increasingly sophisticated methods for the alteration of bony facial form consequent to age, it is imperative that the surgeon have a fundamental knowledge of the age-related changes the skeleton may undergo. To understand these changes better, a detailed anthropometric and histomorphic analysis of the craniofacial skeleton as a function of age was undertaken. The study consisted of a detailed craniometric analysis of 160 skulls selected randomly from a Caucasian population of skeletal remains totaling 1500 specimens. Additionally, a histologic analysis of the supraorbital ridge in a separate preserved cadaver population was performed. Although the results showed individual variation as expected, definite changes in craniofacial morphology were observed. These included (1) appreciable reduction of facial height, most marked in the maxilla and mandible, and strongly correlated with loss of teeth, (2) modest increase in facial width, (3) modest increase in facial depth, except in those regions associated with tooth loss, and (4) general coarsening of bony prominences. Histomorphic analysis demonstrated increasing porosity with age, more marked in the female population. Although these changes represent population trends, in any given patient, any or all of them may be present to varying degrees. Surgeons should be aware of these possibilities and consider selective alterations of the skeletal foundation, either separately or in concert with the overlying soft-tissue envelope, in order to optimize the results of surgery for the aging face.     

An algorithm of facial aging: verification of Lambros's theory by three-dimensional stereolithography, with reference to the pathogenesis of midfacial aging, scleral show, and the lateral suborbital trough deformity

An algorithm of facial aging is presented that serves as the conceptual basis for understanding aesthetic surgical principles and techniques. This model begins with the verification of Lambros's theory of skeletal remodeling. It was suggested that bony changes of the midface may be summarized as a clockwise rotation of the midface relative to the cranial base. Three-dimensional stereolithography/rapid prototyping was used to test this hypothesis. A precisely duplicated facial skeleton was created for young and old men (n = 12) by laser polymerization. Angular measurements confirmed that the angle of the pyriform and maxilla decreased with age (p = 0.004 and 0.005, respectively); there was a trend for the angle of the glabella (frontonasal angle) and orbits to do the same. These results validate Lambros's theory, which serves as a basis to further comprehend the pathogenesis of midfacial aging and the formation of ectropion and scleral show. The algorithm of facial aging is extrapolated from these data, from previous research, and from clinical observation. This model encompasses three main concepts or tenets, and it may serve as a clinical tool for the diagnosis and treatment of facial aging.     

Transconjunctival orbital fat repositioning: transposition of orbital fat pedicles into a subperiosteal pocket

Rejuvenation of the lower eyelid complex is based on the principle that the contour changes characterizing aging involve not only prolapse of orbital fat but also descent of the cheek tissues, resulting in accentuation of the orbital rim and tear trough groove. When a deep groove is present along the orbital rim in the area of the tear trough deformity, it is advantageous, rather than removing orbital fat, to reposition the fat over the orbital rim through the opened arcus marginalis onto the superior face of the maxilla. Orbital fat repositioning can be accomplished through a transconjunctival approach. The arcus marginalis is exposed and incised, and a subperiosteal pocket is created over the superior face of the maxilla. The subperiosteal pocket shape and location are customized based on the desired location of the orbital fat pedicle; often the origins of the levator superioris labialis and the levator alae nasi muscles are partially dissected. Medial and central fat pedicles are created and rotated over the orbital rim into the subperiosteal pocket. A 6-0 polypropylene externalized sutured is used to fixate the fat pedicle in position. The suture can be removed after 3 to 5 days. Twenty-four patients were followed clinically after orbital fat repositioning, with follow-up ranging from 6 to 30 months. Although the fat pedicle undergoes some variable resorption, the viability of the graft, the texture and contour of the repositioned fat after a healing period of 1 to 2 months, and the excellent patient acceptance are indicative of the viability of orbital fat repositioning.     

fras1 shapes endodermal pouch 1 and stabilizes zebrafish pharyngeal skeletal development

Lesions in the epithelially expressed human gene FRAS1 cause Fraser syndrome, a complex disease with variable symptoms, including facial deformities and conductive hearing loss. The developmental basis of facial defects in Fraser syndrome has not been elucidated. Here we show that zebrafish fras1 mutants exhibit defects in facial epithelia and facial skeleton. Specifically, fras1 mutants fail to generate a late-forming portion of pharyngeal pouch 1 (termed late-p1) and skeletal elements adjacent to late-p1 are disrupted. Transplantation studies indicate that fras1 acts in endoderm to ensure normal morphology of both skeleton and endoderm, consistent with well-established epithelial expression of fras1. Late-p1 formation is concurrent with facial skeletal morphogenesis, and some skeletal defects in fras1 mutants arise during late-p1 morphogenesis, indicating a temporal connection between late-p1 and skeletal morphogenesis. Furthermore, fras1 mutants often show prominent second arch skeletal fusions through space occupied by late-p1 in wild type. Whereas every fras1 mutant shows defects in late-p1 formation, skeletal defects are less penetrant and often vary in severity, even between the left and right sides of the same individual. We interpret the fluctuating asymmetry in fras1 mutant skeleton and the changes in fras1 mutant skeletal defects through time as indicators that skeletal formation is destabilized. We propose a model wherein fras1 prompts late-p1 formation and thereby stabilizes skeletal formation during zebrafish facial development. Similar mechanisms of stochastic developmental instability might also account for the high phenotypic variation observed in human FRAS1 patients.     

Tongue evolution in the lungless salamanders, family plethodontidae. I. Introduction, theory and a general model of dynamics.

Plethodontid salamanders capture prey by projecting the tongue from the mouth. An analysis of theoretical mechanics of the hyobranchial skeleton is used to formulate a working hypothesis of tongue movements. Predictions that the skeletal elements of the tongue are included in the projectile and that the hyobranchial skeleton is folded during projection are central to the analysis. When decapitated in a particular way, salamanders project the tongue, and it is not retracted. When these heads are fixed and sectioned, examination confirms the predications. In turn, these observations are used to refine the working hypothesis and to generate a general model of tongue dynamics for plethodontids. Muscles performing the major roles of projection (subarcualis rectus I) and retraction (rectus cervicis profundus) are identified. The skeleton is folded passively along a morphological track having the form of a tractrix. Predictions concerning the shape of the track and the exact configuration of the folded skeleton are confirmed by study of sectioned material. The skeleton unfolds along the track during retraction and is spread into the resting state. The model developed herein will be used as a basis for predictions concerning selection patterns in the family and for analytical purposes in comparative and evolutionary studies.     

Locally released retinoic acid repatterns the first branchial arch cartilages in vivo

The fates of cranial neural crest cells are unique compared to trunk neural crest. Cranial neural crest cells form bone and cartilage and ultimately these cells make up the entire facial skeleton. Previous studies had established that exogenous retinoic acid has effects on neurogenic derivatives of cranial neural crest cells and on segmentation of the hindbrain. In the present study we investigated the role of retinoic acid on the skeletal derivatives of migrating cranial neural crest cells. We wanted to test whether low doses of locally applied retinoic acid could respecify the neural crest-derived, skeletal components of the beak in a reproducible manner. Retinoic acid-soaked beads were positioned at the presumptive mid-hindbrain junction in stage 9 chicken embryos. Two ectopic cartilage elements were induced, the first a sheet of cartilage ventral and lateral to the quadrate and the second an accessory cartilage rod branching from Meckel's cartilage. The accessory rod resembled a retroarticular process that had formed within the first branchial arch domain. In addition the quadrate was often displaced laterally and fused to the retroarticular process. The next day following bead implantation, expression domains of Hoxa2 and Hoxb1 were shifted in an anterior direction up to the mesencephalon and Msx-2 was slightly down-regulated in the hindbrain. Despite down-regulation in neural crest cells, the onset of Msx-2 expression in the facial prominences at stage 18-20 was normal. This correlates with normal distal beak morphology. Focal labeling of neural crest with DiI showed that instead of migrating in a neat group toward the second branchial arch, a cohort of labeled cells from r4 spread anteriorly toward the proximal first arch region. AP-2 expression data confirmed the uninterrupted presence of AP-2-expressing cells from the anterior mesencephalon to r4. The morphological changes can be explained by mismigration of r4 neural crest into the first arch, but at the same time maintenance of their identity. Up-regulation of the Hoxa2 gene in the first branchial arch may have encouraged r4 cells to move in the anterior direction. This combination of events leads to the first branchial arch assuming some of the characteristics of the second branchial arch.     

Craniofacial and mucopolysaccharide abnormalities in Kniest dysplasia

Serial roentgencephalograms of a male patient with Kniest dysplasia were obtained between 1 7/12 and 11 3/12 years of age and were analyzed and compared to cephalometric normative data. The patient displayed macrocephaly with increased size of the neurocranium in all three dimensions. The cranial base angle was significantly flattened, partly as a result of anterior displacement of the sella turcica. The odontoid process was short and wide. At 11 years of age there was bony fusion between the anterior arch of the atlas and the odontoid process as well as between the posterior arch of the atlas and the cranial base. The facial skeleton, including the nasal bones, infra-orbital rims, maxilla and mandible, was retropositioned relative to the anterior cranial base. The mandibular retrognathia was pronounced at an early age but improved with growth. At age 11 years the patient had a straight facial skeletal profile. Examination of the patient's 24-hour urinary excretion of keratan sulfate revealed values markedly elevated for his age. Three additional patients with Kniest dysplasia demonstrated similarly increased excretion of this glycosaminoglycan. The diagnosis of Kniest dysplasia can usually be made from roentgenograms of the extremities, the spine, and the pelvis. However, the morphologic characteristics of the head, as shown by cephalometric analysis, and the increased urinary excretion of keratan sulfate add confirmatory evidence useful in differential diagnosis.     

南京1号直立人头骨与肯尼亚KNM-ER 3733人类头骨化石的形态比较

KNM-ER 3733人类头骨化石的年代为距今1.78百万年,1975年发现于肯尼亚。Walker和Leakey注意到这具头骨与周口店直立人的在脑颅形态上很相近,但二者在年代上相差大约1百万年,故认为直立人形态在这1百万年期间是稳定的。长期来此观点缺乏更多的人类化石证据来支持。1993年在中国发现了南京1号人类头骨化石。该头骨与KNM-ER 3733头骨一样兼具脑颅和面颅,且都属于成年女性个体,但南京1号人类头骨化石的年代比KNM-ER 3733人类头骨化石的要晚大约1百万年。因此,南京1号人类头骨是目前所知的可用来验证直立人头骨形态是否在1百万年期间保持稳定的唯一合适的人类头骨化石材料。形态比较表明,这两个人类头骨化石的脑颅虽然在眶上圆枕上沟的发育程度、眶后收缩的程度、额骨横向隆起的程度、角圆枕和乳后突的发育与否、顶骨形状以及骨壁厚度的表现上有所差异,但有更多的形态性状显示出相近。这些相近表现在脑颅的长、宽、高值上;颅容量上;脑颅的低矮性上;脑颅最大宽之位置上;额骨、顶骨、枕骨之矢弧值的比例上;眶上圆枕的纤细上;顶骨的大小和矢向扁平性上;颞线位置和颞鳞顶缘的形状上;枕鳞的低宽形状上;上枕鳞与下枕鳞之间的转折形状和比例上;枕骨圆枕和枕骨圆枕上沟的发育程度上等。这两具头骨的面颅虽然有同属突颌型的面角、皆发育有鼻骨间嵴、两鼻骨组成的上部宽度与下部宽度皆差别很大,但有更多的形态性状显示出差别。这些差别表现在面型上、颜面上部扁平度上、眶形和眶型上、上颌额突外侧面的朝向上、鼻骨横向隆起程度上、鼻梁外突程度上、鼻型上、颧骨下缘外展程度上、颊高上、颧上颌下缘的形状上、上颌颧突基部的位置上以及颧结节的位置上等。因此,南京1号头骨与KNM-ER 3733头骨之间在脑颅上显示出较多的相近性状,在面颅上则显示出较多的相异性状。脑颅方面的相近性状大多具有分类上的鉴别价值。这两个头骨脑颅形态的相近支持把KNM-ER 3733头骨鉴定为"直立人"的观点;也提示了南京1号头骨的脑颅似乎保持着1百多万年前的"祖先"形态。如果直立人的某些成员在至少1百万年期间保持着形态稳定的话,则这种形态上的稳定主要是表现在脑颅形态上。这两具头骨的面颅形态上较大差异的意义,目前尚不清楚。     

Generating,growing and transforming skeletal shape: insights from amphibian pharyngeal arch cartilages

Amphibians that undergo a metamorphosis provide an unparalleled opportunity to investigate how skeletal shape is generated, preserved, and transformed in development. Their pharyngeal arch (PA) cartilages, which support breathing and feeding behaviors, form embryonically from cranial neural crest cells, grow isometrically at larval stages, and abruptly change shape during metamorphosis. Further, the shape changes occur in three different ways: some adult cartilages form de novo, others emerge from within resorbing larval cartilages and some larval cartilages reshape themselves at the cellular level. Isometric growth followed by abrupt shape change is unique to amphibian PA cartilages, which suggests that the origin and evolution of amphibian metamorphosis has been influenced by the tissue properties of cartilage. This essay reviews the functional role of the PA skeleton in frogs and salamanders and presents a mechanistic framework for understanding how its shape is generated, preserved, and transformed at the levels of cell behavior and specification mechanisms.     

Directed Bmp4 expression in neural crest cells generates a genetic model for the rare human bony syngnathia birth defect

Congenital bony syngnathia, a rare but severe human birth defect, is characterized by bony fusion of the mandible to the maxilla. However, the genetic mechanisms underlying this birth defect are poorly understood, largely due to limitation of available animal models. Here we present evidence that transgenic expression of Bmp4 in neural crest cells causes a series of craniofacial malformations in mice, including a bony fusion between the maxilla and hypoplastic mandible, resembling the bony syngnathia syndrome in humans. In addition, the anterior portion of the palatal shelves emerged from the mandibular arch instead of the maxilla in the mutants. Gene expression assays showed an altered expression of several facial patterning genes, including Hand2, Dlx2, Msx1, Barx1, Foxc2 and Fgf8, in the maxillary and mandibular processes of the mutants, indicating mis-patterned cranial neural crest (CNC) derived cells in the facial region. However, despite of formation of cleft palate and ectopic cartilage, forced expression of a constitutively active form of BMP receptor-Ia (caBmprIa) in CNC lineage did not produce the syngnathia phenotype, suggesting a non-cell autonomous effect of the augmented BMP4 signaling. Our studies demonstrate that aberrant BMP4-mediated signaling in CNC cells leads to mis-patterned facial skeleton and congenital bony syngnathia, and suggest an implication of mutations in BMP signaling pathway in human bony syngnathia.     

Arm joint articulations in the ophiuran brittlestars (Echinodermata: Ophiuroidea): a morphometric analysis of ontogenetic, serial, and interspecific variation

The ophiuroid arm contains a series of vertebral ossicles that form an articulated internal skeleton. Ontogenetic, serial, and interspecific variation in these skeletal elements are investigated using morphometric data from 35 species of brittle-stars (Order Ophiurae). Multiple ossicles were sampled from each individual and several individuals were sampled from each species to reconstruct serial and ontogenetic changes in vertebral morphology. Within species, ontogenetic and serial allometries are not statistically different. These data support 'Jackson's law of localized stages' (Jackson, 1899; Clark, 1914), which proposes that serial variation along the arm reflects ontogenetic stages of ossicle growth.
A multivariate analysis of interspecific variation shows two major vertebral forms: ossicles with a proximal depression and distal keel, and ossicles lacking these features. Variation within these groups is largely continuous, but individual species show distinct shape differences and unique allometric patterns of serial variation. These results suggest that vertebral ossicle variation among species can be described by: 1) variation in initial shape; and 2) variation in the allometric trajectory along the proximal-distal axis.
In all species, the most proximal ossicles within the disk show a non-keeled morphology. In species with keeled arm ossicles, however, there is an abrupt transition within the disk between non-keeled and keeled vertebral forms. A single ossicle, having features of both vertebral types, occurs at this site. The taxonomic distribution of the two vertebral forms and the anatomical transition between forms is discussed with reference to current classification systems and recent phylogenetic schemes for the Ophiuroidea.     

Restoring facial shape in face lifting: the role of skeletal support in facial analysis and midface soft-tissue repositioning

Aesthetic analysis in facial rejuvenation has traditionally been subordinate to technical solutions. While concerns regarding correction of facial laxity, a reduction in the depth of the nasolabial fold, and improvement of both the jowl and the jawline are worthy goals in rhytidectomy, the aesthetic concept of restoring facial shape to a more youthful appearance is equally important. Restoring facial shape in face lifting requires an understanding of how the face ages and then the formulation of a treatment plan that is individualized for the patient. Re-establishment of facial contour is significantly influenced by the re-elevation of descended facial fat through superficial musculoaponeurotic system manipulation; it can be approached through a variety of technical solutions. Underlying skeletal support affects not only the appearance of the face in youth but also how the face ages and influences the operative plan in terms of the requirements for fat repositioning. Formulating a treatment plan that is patient specific and based on the artistic goals as influenced by skeletal support is the key element for consistency in restoring facial shape in face lifting.     

A comparative study of facial growth in Homo and Macaca

Sections were prepared throughout all areas of the various facial bones in young, growing Rhesus monkeys. The detailed distribution of resorptive and depository surfaces and the distribution of endosteal and periosteal bone tissue types were determined. From this information, the sequence of remodeling changes associated with the growth of the facial skeleton was then interpreted. This study is a sequal to previous reports in which growth and remodeling processes in the human face were described using similar procedures. In the present report, growth changes in the monkey and human facial skeleton are compared and contrasted. The general plan of facial growth is similar in both species, but major differences exist in the area of the muzzle. The maxillary arch in the monkey is entirely depository in nature, and it grows in a forward and downward direction as the maxillary tuberosity simultaneously grows backward. In the human, the forward part of the maxillary arch is resorptive in character. This contrasting growth factor results in a downward but not forward movement of this area. The result is decreased prognathism. Other differences in growth pattern exist in the forehead, malar, chin, and orbit. The developmental and phylogenetic basis for the upright human face is discussed and evaluated.     

Interactions between Hox-negative cephalic neural crest cells and the foregut endoderm in patterning the facial skeleton in the vertebrate head

The vertebrate face contains bones that differentiate from mesenchymal cells of neural crest origin, which colonize the median nasofrontal bud and the first branchial arches. The patterning of individual facial bones and their relative positions occurs through mechanisms that remained elusive. During the early stages of head morphogenesis, an endodermal cul-de-sac, destined to become Sessel's pouch, underlies the nasofrontal bud. Reiterative outpocketings of the foregut then form the branchial pouches. We have tested the capacity of endoderm of the avian neurula to specify the facial skeleton by performing ablations or grafts of defined endodermal regions. Neural crest cells that do not express Hox genes respond to patterning cues produced regionally in the anterior endoderm to yield distinct skeletal components of the upper face and jaws. However, Hox-expressing neural crest cells do not respond to these cues. Bone orientation is likewise dependent on the position of the endoderm relative to the embryonic axes. Our findings thus indicate that the endoderm instructs neural crest cells as to the size, shape and position of all the facial skeletal elements, whether they are cartilage or membrane bones.     

Morphing the hyomandibular skeleton in development and evolution

How might changes in developmental regulatory pathways underlie evolutionary changes in morphology? Here we focus on a particular pathway regulated by a secreted, signaling peptide, Endothelin1 (Edn1). Developmental genetic analyses show the Edn1-pathway to be crucial for hyomandibular patterning, and we discuss our work with zebrafish suggesting how the signal may function in regulating numbers of skeletal elements, their sizes and their shapes. We then review a broader collection of comparative studies that examine morphological evolution of a subset of the same skeletal elements-the opercular-branchiostegal series of bones of the hyoid arch. We find that phenotypic changes in zebrafish mutants copy evolutionary changes that recur along many actinopterygian lineages. Hence the developmental genetic studies are informative for providing candidate pathways for macroevolution of facial morphology, as well as for our understanding of how these pathways work.     

Molecular interactions coordinating the development of the forebrain and face

From an architectural point of view, the forebrain acts as a framework upon which the middle and upper face develops and grows. In addition to serving a structural role, we present evidence that the forebrain is a source of signals that shape the facial skeleton. In this study, we inhibited Sonic hedgehog (Shh) signaling from the neuroectoderm then examined the molecular changes and the skeletal alterations resulting from the treatment. One of the first changes we noted was that the dorsoventral polarity of the forebrain was disturbed, which manifested as a loss of Shh in the ventral telencephalon, a reduction in expression of the ventral markers Nkx2.1 and Dlx2, and a concomitant expansion of the dorsal marker Pax6. In addition to changes in the forebrain neuroectoderm, we observed altered gene expression patterns in the facial ectoderm. For example, Shh was not induced in the frontonasal ectoderm, and Ptc and Gli1 were reduced in both the ectoderm and adjacent mesenchyme. As a consequence, a signaling center in the frontonasal prominence was disrupted and the prominence failed to undergo proximodistal and mediolateral expansion. After 15 days of development, the upper beaks of the treated embryos were truncated, and the skeletal elements were located in more medial and proximal locations in relation to the skeletal elements of the lower jaw elements. These data indicate that a role of Shh in the forebrain is to regulate Shh expression in the face, and that together, these Shh domains mediate patterning within the frontonasal prominence and proximodistal outgrowth of the middle and upper face.     

Exencephaly and axial skeletal dysmorphogenesis induced by maternal exposure to cadmium in the mouse

To investigate the axial skeletal dysmorphogenesis associated with exencephaly and facial abnormalities, two doses of cadmium chloride (4 mg/kg and 6 mg/kg) were administered subcutaneously to MF1 mice on day 7 of gestation (sperm-positive day = day 0). Fetuses were collected on day 18. Gross examination revealed a very high incidence of cranioschisis aperta with exencephaly, maxillary and mandibular hypoplasia, low-set microtia, edema, and growth retardation of fetuses in both treatment groups. Alizarin red S-stained and cleared skeletal preparations of these embryos revealed hypoplasia of the premaxilla, maxilla, nasal bone, zygoma, and mandible of the facial skeleton. The orbital plate represented the frontal bone. The vault of the skull was conspicuously absent. In cranioschisis, the exoccipitals had splayed and fused with the atlas. The basicranial bones were hypoplastic and crowded, thus reducing the cranial cavity. The vertebral bodies were more affected than the arches. Hemivertebrae and longitudinal fusion of centra and arches were also noted. The ribs were usually rudimentary. Agenesis, fusion, and forking of ribs were frequently observed. The sternebrae were rudimentary, bipartite, or longitudinally fused. These data clearly establish the association between neural tube and axial mesodermal abnormalities and emphasize the interdependence of the neurectoderm and mesoderm in normal morphogenesis.     

Energy of dissociation of lipid bilayer from the membrane skeleton of red blood cells

The association between the lipid bilayer and the membrane skeleton is important to cell function. In red blood cells, defects in this association can lead to various forms of hemolytic anemia. Although proteins involved in this association have been well characterized biochemically, the physical strength of this association is only beginning to be studied. Formation of a small cylindrical strand of membrane material (tether) from the membrane involves separation of the lipid bilayer from the membrane skeleton. By measuring the force required to form a tether, and knowing the contribution to the force due to the deformation of a lipid bilayer, it is possible to calculate the additional contribution to the work of tether formation due to the separation of membrane skeleton from the lipid bilayer. In the present study, we measured the tethering force during tether formation using a microcantilever (a thin, flexible glass fiber) as a force transducer. Numerical calculations of the red cell contour were performed to examine how the shape of the contour affects the calculation of tether radius, and subsequently separation work per unit area W(sk) and bending stiffness k(c). At high aspiration pressure and small external force, the red cell contour can be accurately modeled as a sphere, but at low aspiration pressure and large external force, the contour deviates from a sphere and may affect the calculation. Based on an energy balance and numerical calculations of the cell contour, values of the membrane bending stiffness k(c) = 2.0 x 10(-19) Nm and the separation work per unit area W(sk) = 0.06 mJ/m2 were obtained.