Role of Matrix Gla protein in midface development: Recent advances.

Craniofacial development is a delicate process that involves complex interactions among cells of multiple developmental origins, their migration, proliferation, and differentiation. Tissue morphogenesis of the craniofacial skeleton depends on genetic and environmental factors, and on specific signaling pathways, which are still not well understood. Developmental defects of the midface caused by the absence, delays, or premature fusion of nasal and maxillary prominences vary in severity; leading to clefts, hypoplasias, and midline expansion. In the current review, we focus on the importance of the chondrocranium in craniofacial growth and how its impaired development leads to midface hypoplasia. More importantly, we reported how Matrix Gla protein (MGP), a potent inhibitor of extracellular matrix mineralization, facilitates midface development by preventing ectopic calcification of the nasal septum. In fact, MGP may act as a common link in multiple developmental pathologies all showing midface hypoplasia caused by abnormal cartilage calcification. This brief review discusses the gap in knowledge in the field, raises pertinent questions, which remain unanswered, and sheds light on the future research directions.

Real-time monitoring of the growth of the nasal septal cartilage and the nasofrontal suture.

INTRODUCTION: The nasal septum is thought to be a primary growth cartilage for the midface and, as such, has been implicated in syndromes involving midfacial hypoplasia. However, this internal structure is difficult to study directly. The aims of this study were to provide direct, continuous measurements of the growth of the nasal septal cartilage and to compare these with similar measurements of the nasofrontal suture to test whether the growth of the cartilage precedes the growth of the suture and whether the growth of the septal cartilage is constant or episodic. METHODS: Ten Hanford minipigs were used. Linear displacement transducers were implanted surgically in the septal cartilage and across the nasofrontal suture. Length measurements of the cartilage and suture were recorded telemetrically each minute for several days. RESULTS: The growth rate of the nasal septal cartilage (0.07% ± 0.03% length/h) was significantly higher than that of the suture (0.03% ± 0.02% length/h) (P = 0.004). The growth of both structures was episodic with alternating periods of growth (5-6 per day) and periods of stasis or shrinkage. No diurnal variation in growth of the cartilage was detected. CONCLUSIONS: These results are consistent with the notion that growth of the septal cartilage might drive growth of the nasofrontal suture. Growth of the midface is episodic rather than constant.

Shaping skeletal growth by modular regulatory elements in the Bmp5 gene.

Cartilage and bone are formed into a remarkable range of shapes and sizes that underlie many anatomical adaptations to different lifestyles in vertebrates. Although the morphological blueprints for individual cartilage and bony structures must somehow be encoded in the genome, we currently know little about the detailed genomic mechanisms that direct precise growth patterns for particular bones. We have carried out large-scale enhancer surveys to identify the regulatory architecture controlling developmental expression of the mouse Bmp5 gene, which encodes a secreted signaling molecule required for normal morphology of specific skeletal features. Although Bmp5 is expressed in many skeletal precursors, different enhancers control expression in individual bones. Remarkably, we show here that different enhancers also exist for highly restricted spatial subdomains along the surface of individual skeletal structures, including ribs and nasal cartilages. Transgenic, null, and regulatory mutations confirm that these anatomy-specific sequences are sufficient to trigger local changes in skeletal morphology and are required for establishing normal growth rates on separate bone surfaces. Our findings suggest that individual bones are composite structures whose detailed growth patterns are built from many smaller lineage and gene expression domains. Individual enhancers in BMP genes provide a genomic mechanism for controlling precise growth domains in particular cartilages and bones, making it possible to separately regulate skeletal anatomy at highly specific locations in the body.

Secondary Rhinoplasty for Unilateral Cleft Nasal Deformity.

BACKGROUND: Secondary cleft rhinoplasty presents some of the most challenging cases of both cosmetic and functional nasal deformities. Understanding the anatomy and growth abnormality seen with the cleft nasal deformity helps to tailor surgical management. This article seeks to expand on the application of current concepts in secondary rhinoplasty for unilateral cleft lip nasal deformity. METHODS: The authors review nasal analysis in the cleft rhinoplasty patient and provide the surgical management for each aspect in the secondary cleft rhinoplasty. RESULTS: The secondary rhinoplasty was divided into seven areas: piriform hypoplasia, septal reconstruction, dorsal reshaping, tip reshaping, tip projection, alar reshaping, and alar repositioning. Surgical management for each is provided. CONCLUSION: Secondary cleft rhinoplasty requires an understanding of the structural dysmorphology, and the use of cosmetic, functional, and secondary rhinoplasty techniques for its successful management.

[Chondroblast proliferative activity study in forming big alar cartilage].

Study was performed of chondroblast proliferative activity peculiarities on early stages of big alar cartilage forming. The reaction with monoclonal antibodies towards proliferating cell nuclear antigen in alar cartilage of human embryo and newly born infant rat testified to 2 cartilage growth types - appositional and interstitial. Cells proliferative activity did not depend upon their location on inner or outer side of nasal cartilaginous plate thereby not conforming existent in the literature opinion about the presence of special zones of cartilaginous tissue primary new formation in human nasal cartilage on early stages of its ontogeny.

Signals from the brain and olfactory epithelium control shaping of the mammalian nasal capsule cartilage.

Facial shape is the basis for facial recognition and categorization. Facial features reflect the underlying geometry of the skeletal structures. Here, we reveal that cartilaginous nasal capsule (corresponding to upper jaw and face) is shaped by signals generated by neural structures: brain and olfactory epithelium. Brain-derived Sonic Hedgehog (SHH) enables the induction of nasal septum and posterior nasal capsule, whereas the formation of a capsule roof is controlled by signals from the olfactory epithelium. Unexpectedly, the cartilage of the nasal capsule turned out to be important for shaping membranous facial bones during development. This suggests that conserved neurosensory structures could benefit from protection and have evolved signals inducing cranial cartilages encasing them. Experiments with mutant mice revealed that the genomic regulatory regions controlling production of SHH in the nervous system contribute to facial cartilage morphogenesis, which might be a mechanism responsible for the adaptive evolution of animal faces and snouts.

Strategies to Mitigate Variability in Engineering Human Nasal Cartilage.

Skin cancer and its associated treitments can have devastating consequences for survivors; this is particularly true when cancer occurs on the nose. Recent work has applied cell-based tissue engineering (TE) strategies to develop nasal cartilage constructs for reconstruction of the nose. In this study, we have generated human nasal cartilage on a clinically approved collagen scaffold to investigate the donor-to-donor variability of TE cartilage and evaluated strategies to mitigate it. We also evaluated the gene expression of the family of fibroblast growth factor receptors (FGFR1-4) and their association with tissue quality. FGFR 1 was significantly positively correlated with GAG/DNA; a measure of chondrogenic capacity. We implemented two strategies: hypoxic culture and co-culture with mesenchymal stromal cells (MSCs) to increase tissue quality. Total glycosaminoglycan (GAG) content varied significantly between donors initially, with >10-fold difference between the best and worst donor tissue. Our co-culture strategy was able to increase TE construct quality from poor quality donor tissue while supressing hypertrophy relative to MSCs alone. However, no differences were observed with the use of hypoxic culture. Tissues generated using co-culture with MSCs became vascularized and calcified in vivo, demonstrating a non-stable cartilage phenotype in co-culture and MSCs cartilage constructs.

Septoplasty in children.

OBJECTIVES: Physicians have long had concerns about the potential harmful effects of pediatric septoplasties on the nasoseptal growth process because septal cartilage is important for the growth and development of the face. METHODS: In this review article, pediatric septoplasty and its indications are discussed, together with a literature survey. In addition, overviews of development of the nasal skeleton from neonate to adult, nasal growth, and cartilaginous septum are presented. Important issues and comments on pediatric septoplasties are provided. RESULTS: During septoplasty procedures, elevation of the mucoperichondrium unilaterally or bilaterally does not negatively affect growth of the face. Stabilization of the septum may be easier when mucosal elevation is performed unilaterally. The nasal floor mucosa should not be elevated so to avoid damage to the incisive nerves. Corrections and limited excisions may be done from the cartilaginous septum. Separation of the septal cartilage from the perpendicular plate, especially at the dorsal part, should not be performed because this area is important for the length and height of the nasal septum and nasal dorsum. Incisions or excisions should not be performed through the growing and supporting zones, especially at the sphenoethmoid dorsal zone. CONCLUSION: If there are severe breathing problems related to the septal deviation, septoplasty should be performed. In the majority of cases, septal surgery may be conducted in 6-year-old children. However, if necessary, septal surgery may be performed in younger children and even at birth.

Longitudinal study of cephalometric soft tissue profile traits between the ages of 6 and 18 years.

OBJECTIVE: To study the longitudinal changes in 19 soft tissue cephalometric traits (according to the Bergman cephalometric soft tissue facial analysis). MATERIALS AND METHODS: Cephalograms and photographs of 40 subjects (20 male, 20 female, from the Burlington Growth Centre) that were obtained at ages 6, 9, 12, 14, 16, and 18 years were used. Subjects were orthodontically untreated whites and had Class I dentoskeletal relationships (ideal overjet and overbite). Images were obtained with the lips in a relaxed position or lightly touching. RESULTS: Three groups of soft tissue traits were identified: (1) traits that increased in size with growth (nasal projection, lower face height, chin projection, chin-throat length, upper and lower lip thickness, upper lip length, and lower lip-chin length); (2) traits that decreased in size with growth (interlabial gap and mandibular sulcus contour [only in females]); and (3) traits that remained relatively constant during growth (facial profile angle, nasolabial angle, lower face percentage, chin-throat/lower face height percentage, lower face-throat angle, upper incisor exposure, maxillary sulcus contour, and upper and lower lip protrusion). CONCLUSION: Current findings identify areas of growth and change in individuals with Class I skeletal and dental relationships with ideal overjet and overbite and should be considered during treatment planning of orthodontic and orthognathic patients.

Are gender differences in external noses caused by differences in nasal septal growth?

BACKGROUND: The nasal septum plays an important role in nasal growth, but there have been few reports on the relationship between the septum and nasal growth. The authors investigated the relationship between septa and external noses using computed tomography during the growth period. METHODS: One hundred and ninety-eight patients under the age of 21 were enrolled in this study between 2008 and 2012. The authors evaluated a total of 9 measurement items (five for nasal bones and septa, and four for external noses). RESULTS: In the final age group, most measurement items were significantly larger in males than in females. However, there was no remarkable difference between male and female growth processes. Nasal bridge length and nasal height were significantly correlated with the nasal bone or septum in almost all age groups. The relative proportion of the cartilaginous septum decreased significantly with age, and was negatively correlated with the perpendicular plate in all age groups. CONCLUSIONS: Nasal septa and external noses were both larger in males than in females at the beginning of the study period, although not significantly. The differences became significant throughout the study due to differential increases between the sexes during the monitored growth spurts.

Cleft lip, nose, and palate: the nasal septum as the pacemaker for midfacial growth.

The need to be aware of the dynamics of cartilage development and growth is encountered by surgeons whenever they attempt to correct craniofacial defects such as unilateral or bilateral cleft lip/cleft palate or midfacial injuries after trauma. Within the craniofacial region, the nasal septal cartilage and the sphenoethmoidal and sphenooccipital cranial synchondroses are distinguished from other craniofacial cartilages in possessing intrinsic growth potential. Indeed, growth of the nasal septal cartilage outstrips the growth of other skeletal and soft tissues in the midface to such an extent that it is the pacemaker for growth of the face and anterior portion of the skull. We revisit and reinforce the importance of the nasal septum as pacemaker with analysis of 3 classes of evidence: in vivo growth of the nasal septum in nonhuman mammalian models; composition and in vitro growth of nasal septal cartilage or chondrocytes; and experience from the surgical repair of unilateral or bilateral facial clefts.

Secondary cleft nasoplasty at primary school age: quantitative evaluation of the efficacy of resorbable plates.

BACKGROUND: Secondary cleft nasal deformity in children of primary school age can result in permanent impact to a child's self-esteem. The ideal technique and timing of addressing the deformity remain controversial, as harvest of septal cartilage affects nasal growth and limits future options. METHODS: Fifty-three patients underwent secondary cleft nasoplasty with resorbable plate placement as a columellar strut. All patients had standardized preoperative and postoperative photographs. Basilar photographs were analyzed for height and width of each nostril, height and width of the nose, and deviation of the nasal tip from midline. RESULTS: In unilateral clefts, improvements in nostril width, nostril height, tip height, and tip deviation were found to be statistically significant in early postoperative photographs; improvements in nostril height, tip height, and tip deviation remained statistically significant in late photographs. In patients with bilateral clefts, improvements in nostril height and tip height were found to be significant in early postoperative photographs, with improvement in nostril height remaining significant in the long term. Partial plate exposure limited to the columellar base occurred in five patients (9.4 percent), successfully treated in the clinic setting with no loss of nasal tip support. CONCLUSIONS: The authors provide quantitative data regarding nasal outcomes following secondary cleft nasoplasty using resorbable plates for tip support. Significant long-term improvements in nasal appearance are possible using this technique with minimal complications. In those patients presenting with cleft nasal deformity at primary school age, the use of resorbable plates can improve nasal symmetry and spare native cartilage and thereby reduce the potential for nasal growth disturbance. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

The morphological features and developmental changes of the philtral dimple: a guide to surgical intervention in cases of cleft lip.

OBJECTIVE: This study was undertaken to analyse in detail the morphological features of the philtral dimple and the developmental changes of philtral morphology, including a comparison with patients with a cleft lip. PATIENTS AND PARTICIPANTS: Fifty-five normal Japanese adults, seventy-five children and fifteen patients with complete unilateral cleft lip were referred for analysis. DESIGN: 3D facial data were acquired with a non-contacting laser scanner. We calculated the desired linear and angular components, defining the features of the philtrum with analysing software. RESULTS: The philtral dimple was morphologically expressed by the two different deepest points in the horizontal and sagittal sectional view, respectively. These decreased with age and did not show any correlation. In contrast, philtral measurements on the X-Y coordinates increased during the course of development. Most of the linear and angular variables in the patients with the cleft lip had exhibited greater values than the normal subjects, reflecting the deformed philtral morphology. CONCLUSIONS: To obtain an optimally natural philtral construction accompanied by a symmetrical lip in cleft surgery, it is critical to take into consideration both the geometric features of the philtral depth and age-appropriate morphological features of the philtrum as objective criteria.

[Influence of different surgeries on growth and development of alar cartilage in young-rabbit].

OBJECTIVE: The purpose of this study is to observe the affection of different clinical surgeries on alar nasal cartilages' growth and development. The experimental results can provide some theory basis for clinical surgeries. METHOD: Twenty-eight New Zealand immature rabbits were used in this study, and divided into normal control group, hidden dissection group and cutting off alar nasal cartilages group randomly, which included 4,12 and 12 rabbits, separately. Arc incision were made on the mucous membrane of nasal cavity,and then dissect the alar nasal cartilages hidden or cut off the alar nasal cartilages, separately. The growth and development of the alar cartilage were observed at different stages after the surgery using histological and immuno-histochemical methods. RESULT: Four weeks, eight weeks, twelve weeks and sixteen weeks after surgery, there were no significant differences in the indexes of chondrocytes between hidden dissection group and control group. In cutting off alar nasal cartilages group, fiber tissue were observed in the vacancy left after being cut off cartilages, and even mucous membrane tissue could be seen in some slices. CONCLUSION: There is no adverse influence on the growth and development of the alar cartilage after being hidden dissected. Contrarily, the restoring capability of transparent cartilage cannot counteract the injury resulted form the surgery after the alar nasal cartilages being cut off.

Development of the ethmoidal structures of the endocranium in Discoglossus pictus (Anura: Discoglossidae).

We use histological techniques and computer-aided three-dimensional reconstructions made from serial histological sections to describe the ontogeny of the ethmoidal endocranium of discoglossid frog Discoglossus pictus. We identify a pattern of development for the suprarostral cartilage that differs from previous findings and probably represents the ancestral anuran pattern. The nasal cartilages, including the inferior prenasal cartilage, are de novo adult structures. The only larva-derived structures of the adult nasal capsules are the posterior aspects of the solum nasi and septum nasi. We also identify patterns of development for the ethmoid plate and postnasal wall that occur during early in ontogenesis. These patterns are associated with development events during metamorphic climax. The pattern of timing of chondrification of the anterior nasal cartilages more closely coincides with that of the neobatrachian species than that recorded for the pelobatid frog Spea. In addition, this study supports a sister taxon relationship between Discoglossus and Alytes.