Gene/environment interactions in craniosynostosis: A brief review.

It is suggested that craniosynostosis is caused by a heterogeneous set of effects including gene mutations, teratogenic exposure during critical periods of development and gene/environment interactions. Distinguishing between sufficient, additive and interactive effects is important to the study of gene/environment interactions and allows for segregation of environmental exposures effecting susceptible populations. Through the identification of sufficient and interactive effects, efforts in prevention of craniosynostosis may be successful. Here, we provide a brief review focusing on defining these categorized exposures and relevant literature that has interrogated gene/environment interactions for craniosynostosis.

Transforming Growth Factor-ß3 Therapy Delays Postoperative Reossification and Improves Craniofacial Growth in Craniosynostotic Rabbits.

Postoperative reossification is a common clinical correlate following surgery. It has been suggested that an underexpression of transforming growth factor-ß3 (TGF-ß3) may be related to craniosynostosis and postoperative reossification. Adding TGF-ß3 may delay reossification and improve postoperative growth. The present study was designed to test this hypothesis. Thirty 10-day-old New Zealand white rabbits with hereditary coronal suture synostosis were divided into three groups: (1) suturectomy controls (n = 14), (2) suturectomy treated with bovine serum albumin (n = 8), and (3) suturectomy treated with TGF-ß3 protein (n = 8). At 10 days of age, a 3-mm × 15-mm coronal suturectomy was performed, and serial three-dimensional (3D) computed tomography (CT) scans and cephalographs were taken at 10, 25, 42, and 84 days of age. Calvaria were harvested at 84 days of age for histomorphometric analysis. Mean differences were analyzed using a group by age analysis of variance. Analysis of the 3D CT scan data revealed that sites treated with TGF-ß3 had significantly (P < .05) greater defect areas and significantly (P < .05) greater intracranial volumes through 84 days of age compared with controls. Histomorphometry showed that sites treated with TGF-ß3 had patent suturectomy sites and significantly (P < .001) less new bone in the suturectomy site compared with controls. Serial radiograph data revealed significant (P < .05) differences in craniofacial growth from 25 to 84 days in TGF-ß3-treated rabbits compared with controls. Data show that TGF-ß3 administration delayed reossification and improved craniofacial growth in this rabbit model. These findings also suggest that this molecular-based therapy may have potential clinical use.

The effects of testosterone on craniosynostotic calvarial cells: a test of the gene/environmental model of craniofacial anomalies.

INTRODUCTION: The gene-environmental interaction model for craniofacial development proposes that if a genetic predisposition for an anomaly is coupled with an environmental factor that can exacerbate this predisposition, more severe phenotypes will result. Here, we utilize cells derived from our non-syndromic rabbit model of craniosynostosis to test the hypothesis that an insult, testosterone (TP) administration (exogenous source) will alter the osteogenic activity of these cells. DESIGN: Calvarial cells from wild-type (WT) (N=13) or craniosynostotic (CS) rabbits (N=11) were stimulated with TP, an androgen receptor blocker, flutamide, and combined treatments. Proliferation and differentiation assays were conducted after 7 days. anova and t-tests were used to determine differences in stimulation and cell type. RESULTS: The CS cells had significantly greater proliferation after TP administration compared to WT. There were no appreciable changes in differentiation after TP stimulation. Flutamide administration or combined TP and flutamide administration decreased both proliferation and differentiation for both cell types similarly. CONCLUSIONS: Testosterone exposure caused an increase in cell proliferation for CS osteoblast cells. However, a therapy targeted to mitigate this response (flutamide therapy) similarly affected CS and WT cells, suggesting that the administration of flutamide or TP in the presence of flutamide decreases osteogenesis of these cells. Thus, although our data support a mechanism of gene-environmental interaction, these results would not support a therapeutic intervention based on this interaction.

Effects of nicotine exposure on murine mandibular development.

Nicotine is known to affect cell proliferation and differentiation, two processes vital to proper development of the mandible. The mandible, the lower jaw in mammals and fish, plays a crucial role in craniofacial development. Malformation of the jaw can precipitate a plethora of complications including disrupting development of the upper jaw, the palate, and or impeding airway function. The purpose of this study was to test the hypothesis that in utero nicotine exposure alters the development of the murine mandible in a dose dependent manner. To test this hypothesis, wild type C57BL6 mice were used to produce in utero nicotine exposed litters by adding nicotine to the drinking water of pregnant dams at concentrations of 0 µg/ml (control), 50 µg/ml (low), 100 µg/ml (medium), 200 µg/ml (high) throughout pregnancy to birth of litters mimicking clinically relevant nicotine exposures. Resultant pups revealed no significant differences in body weight however, cephalometric investigation revealed several dimensions affected by nicotine exposure including mandibular ramus height, mandibular body height, and molar length. Histological investigation of molars revealed an increase in proliferation and a decrease in apoptosis with nicotine exposure. These results demonstrate the direct effects of nicotine on the developing mandible outside the context of tobacco use, indicating that nicotine use including tobacco alternatives, cessation methods, and electronic nicotine delivering products may disrupt normal growth and development of the craniofacial complex.

Suprafibromuscular facelifting with periosteal suspension of the superficial musculoaponeurotic system and fat pad of Bichat rotation. Tightening the net.

OBJECTIVE: To design a facelifting technique that improves the safety of the facial nerve in extended facelifting; improves methods of fixation of the elevation of the nasolabial folds, the melolabial folds, the corner of the mouth and the malar fat pad; and augments the malar and submalar areas without implants. DESIGN: After a retrospective review of previous modified "composite" technique facelift results (307 patients over 4 years), a suprafibromuscular facelift technique was evolved through 22 fresh cadaver dissections. The resulting technique was applied to 73 patients, 61 females and 12 males, who were followed up for 6 to 18 months. METHODS: Preauricular dissection was subcutaneous for about 4 cm. An incision was made through the superficial musculoaponeurotic system (SMAS) at the level of the body of the zygoma. Dissection over the malar eminence was performed under the orbicularis muscle. Mid-cheek dissection was performed over the fibromuscular SMAS in th layer of areolar tissues that lines it. A rotation of the fat pad of Bichat (or buccal fat pad) was used, when indicated, to augment the cheek. Stabilization of the elevation of the nasolabial fold, the melolabial fold, and the corner of the mouth was obtained by the use of suspension sutures from the SMAS to the malar eminence. Stabilization of the malar fat pad was provided by the laterally directed flap of SMAS that was sutured to the temporal fascia. The patients were followed up for 6 to 18 months and evaluated for stability of the correction and facial nerve complications. RESULTS AND CONCLUSION; The facelift corrections (nasolabial fold, melolabial fold, malar fat pad shift) were stable over the follow-up period. No facial nerve injuries were seen.

Development of the Lacrimal Apparatus in the Rabbit (Oryctolagus cuniculus) and Its Potential Role as an Animal Model for Humans.

Rabbits have been proposed as a model organism for the human lacrimal apparatus (LA), including the nasolacrimal duct (NLD), based principally on comparative studies of adult morphology; however, little is known about its development. The NLD first appears as an incomplete primordium in the subcutaneous region of the primordial eyelid and subsequently elongates to reach the naris. One posterior and three anterior orbital glands are present fetally although one of the anterior glands is soon lost. The NLD follows a tortuous path and passes through a bony canal consisting of lacrimal, maxilla, and maxilloturbinal bones at different regions. Although early developmental similarities exist to haplorhine primates, the narial opening of the NLD resembles strepsirrhines. This distinction, along with the ductal and glandular differences at the orbital end of the NLD, indicates that rabbits may be a poor model for LA drainage in primates, specifically humans.