Proboscis Lateralis: A Unique Window into Nasal Embryology.

Proboscis lateralis is a rare congenital nasal deformity often associated with other nasal or ocular deformities. This anomaly offers a unique window into nasal embryology.

Midface and upper airway dysgenesis in FGFR2-related craniosynostosis involves multiple tissue-specific and cell cycle effects.

Midface dysgenesis is a feature of more than 200 genetic conditions in which upper airway anomalies frequently cause respiratory distress, but its etiology is poorly understood. Mouse models of Apert and Crouzon craniosynostosis syndromes exhibit midface dysgenesis similar to the human conditions. They carry activating mutations of Fgfr2, which is expressed in multiple craniofacial tissues during development. Magnetic resonance microscopy of three mouse models of Apert and Crouzon syndromes revealed decreased nasal passage volume in all models at birth. Histological analysis suggested overgrowth of the nasal cartilage in the two Apert syndrome mouse models. We used tissue-specific gene expression and transcriptome analysis to further dissect the structural, cellular and molecular alterations underlying midface and upper airway dysgenesis in Apert Fgfr2+/S252W mutants. Cartilage thickened progressively during embryogenesis because of increased chondrocyte proliferation in the presence of Fgf2 Oral epithelium expression of mutant Fgfr2, which resulted in a distinctive nasal septal fusion defect, and premature facial suture fusion contributed to the overall dysmorphology. Midface dysgenesis in Fgfr2-related craniosynostosis is a complex phenotype arising from the combined effects of aberrant signaling in multiple craniofacial tissues.

[Diagnostic and therapeutic interest of studying the nose in maxillo-dento-facial orthopedics]. / Intérêt diagnostique et thérapeutique de l'étude du nez en orthopédie dento-maxillo-faciale.

INTRODUCTION: Orthodontists have long tried to predict future growth. It is one of the most difficult goals to achieve precisely despite the different methods of growth forecasting. A simple technique based on clinical and radiological analyses of the nose and premaxilla makes it possible, using no measurements, to accurately predict future maxillary growth and to deduce the therapeutic indications. A morphologic study of the nose is also an important item in the diagnosis of cranio-facial syndromes. MATERIALS AND METHODS: Combining detailed semiologic and radiologic studies of the nasal and premaxillary structures, this article proposes a method for evaluating and predicting facial growth. RESULTS: Experience based on many observations and current embryological knowledg can detect growth abnormalities of the ethmoïdo-nasal-premaxillary unit and provide valuable therapeutic information. DISCUSSION: Combining clinical and radiologic analyses of nasal and premaxillary morphology is a good method to predict growth of the upper face. It is also an important feature in the diagnosis of cranio-facial syndromes. CONCLUSION: This technique should be included in the diagnosis of maxillo-dento-facial orthopedic cases.

Face morphogenesis is promoted by Pbx-dependent EMT via regulation of Snail1 during frontonasal prominence fusion.

Human cleft lip with or without cleft palate (CL/P) is a common craniofacial abnormality caused by impaired fusion of the facial prominences. We have previously reported that, in the mouse embryo, epithelial apoptosis mediates fusion at the seam where the prominences coalesce. Here, we show that apoptosis alone is not sufficient to remove the epithelial layers. We observed morphological changes in the seam epithelia, intermingling of cells of epithelial descent into the mesenchyme and molecular signatures of epithelial-mesenchymal transition (EMT). Utilizing mouse lines with cephalic epithelium-specific Pbx loss exhibiting CL/P, we demonstrate that these cellular behaviors are Pbx dependent, as is the transcriptional regulation of the EMT driver Snail1. Furthermore, in the embryo, the majority of epithelial cells expressing high levels of Snail1 do not undergo apoptosis. Pbx1 loss- and gain-of-function in a tractable epithelial culture system revealed that Pbx1 is both necessary and sufficient for EMT induction. This study establishes that Pbx-dependent EMT programs mediate murine upper lip/primary palate morphogenesis and fusion via regulation of Snail1. Of note, the EMT signatures observed in the embryo are mirrored in the epithelial culture system.

Masses of the Nose, Nasal Cavity, and Nasopharynx in Children.

A wide range of masses develop in the nose, nasal cavity, and nasopharynx in children. These lesions may arise from the nasal ala or other structures of the nose, including the mucosa covering any surface of the nasal cavity, the cartilaginous or osseous portion of the nasal septum, the nasal turbinates, and the nasal bones. Lesions may also arise from the nasopharynx or adjacent structures and involve the nose by way of direct extension. The causes of nasal masses in children include congenital and developmental disorders such as congenital nasolacrimal duct mucocele, dermoid cyst, cephalocele, and nasal neuroglial heterotopia; inflammatory and infectious processes such as mucocele, polyp, and pyogenic granuloma; benign neoplasms such as infantile hemangioma and juvenile nasopharyngeal angiofibroma; malignant lesions such as rhabdomyosarcoma and nasopharyngeal carcinoma; and masses related to prior trauma such as septal hematoma. Although direct visualization, without imaging, is frequently sufficient to diagnose pediatric nasal conditions, in many cases imaging has a key role in the treatment of the affected child. Some of these lesions have characteristic computed tomography and/or magnetic resonance imaging findings, some of them are diagnosed on the basis of the location and imaging findings combined, and others demonstrate nonspecific imaging findings. However, imaging is important for better defining the total extent of the lesion and guiding the clinician in determining whether medical and/or surgical intervention is required. In this article, the authors review the imaging findings of the most common causes-and many of the not-so-common causes-of nasal masses encountered in the pediatric population. ©RSNA, 2017.

Supernumerary Nostril: Two Years Follow-Up.

Supernumerary nostril is a very rare congenital anomaly of the nose. Since the first patient reported by Lindsay in 1906, few number of patients were reported in the literature. Various types had been described with different surgical modalities for correction. It can be isolated or associated with other malformations such as facial cleft, esophageal atresia, and imperforate anus. Most of the patients are unilateral, but it may be bilateral. It may have a communication with a normal nasal cavity or not.In this study, the authors present a case of a 1-year-old male with a positive perinatal history of teratogen exposure had isolated supernumerary left nostril with communication to the nasal cavity.The authors will discuss different theories related to supernumerary nostril development, differences between published reports, the proposed surgical techniques, and the outcome of their treatment approach.

Augmented BMP signaling in the neural crest inhibits nasal cartilage morphogenesis by inducing p53-mediated apoptosis.

Bone morphogenetic protein (BMP) signaling plays many roles in skull morphogenesis. We have previously reported that enhanced BMP signaling through the BMP type IA receptor (BMPR1A) in cranial neural crest cells causes craniosynostosis during postnatal development. Additionally, we observed that 55% of Bmpr1a mutant mice show neonatal lethality characterized by a distended gastrointestinal tract. Here, we show that severely affected mutants exhibit defective nasal cartilage, failure of fusion between the nasal septum and the secondary palate, and higher levels of phosphorylated SMAD1 and SMAD5 in the nasal tissue. TUNEL demonstrated an increase in apoptosis in both condensing mesenchymal tissues and cartilage of the nasal region in mutants. The levels of p53 (TRP53) tumor suppressor protein were also increased in the same tissue. Injection of pifithrin-α, a chemical inhibitor of p53, into pregnant mice prevented neonatal lethality while concomitantly reducing apoptosis in nasal cartilage primordia, suggesting that enhanced BMP signaling induces p53-mediated apoptosis in the nasal cartilage. The expression of Bax and caspase 3, downstream targets of p53, was increased in the mutants; however, the p53 expression level was unchanged. It has been reported that MDM2 interacts with p53 to promote degradation. We found that the amount of MDM2-p53 complex was decreased in all mutants, and the most severely affected mutants had the largest decrease. Our previous finding that the BMP signaling component SMAD1 prevents MDM2-mediated p53 degradation coupled with our new data indicate that augmented BMP signaling induces p53-mediated apoptosis by prevention of p53 degradation in developing nasal cartilage. Thus, an appropriate level of BMP signaling is required for proper craniofacial morphogenesis.

Evidence-based medicine: Unilateral cleft lip and nose repair.

LEARNING OBJECTIVES: After reading this article, the participant should be able to: 1. Describe the anatomical malformations found in unilateral cleft lip deformity. 2. Discuss current methods of measuring the deformity and subsequent outcomes. 3. Discuss preoperative assessments, workup, and the use of early interventions before definitive cheiloplasty (e.g., preoperative orthopedics, lip adhesion). 4. Discuss the different techniques used for cheiloplasty and nasal repair. 5. Discuss the use of postoperative splints, taping, or molding. 6. Discuss the outcomes and evidence of cleft lip repairs and identify areas for future research. SUMMARY: The Maintenance of Certification module series is designed to help clinicians structure their individualized course of study to specific areas appropriate to their clinical practice. This article was prepared to accompany practice-based assessment of preoperative evaluation, anesthesia, surgical treatment plan, perioperative management, and outcomes. In this format, the clinician is invited to compare his or her methods of patient assessment and treatment, outcomes, and complications, with authoritative, information-based references. This information base is then used for self-assessment and benchmarking in parts II and IV of the Maintenance of Certification process of the American Board of Plastic Surgery. This article is not intended to be an exhaustive treatise on the subject. Rather, it is designed to serve as a reference point for further in-depth study by review of the reference articles presented.

Anatomy research of nasolabial muscle structure in fetus with cleft lip: an iodine staining technique based on microcomputed tomography.

A thorough knowledge of the anatomic structure of the orbicularis oris of the upper lip and the nasalis in fetus with cleft lip is the key for the success of cleft lip repair. To understand the anatomic structure of the muscles of nasolabial region in fetus with cleft lip, the nasolabial tissues in 4 aborted fetuses with cleft lip were soaked for 7 days with iodine solution (Lugol solution of 3.75%) and were given micro-computed tomography. After the iodine solution permeated into the soft tissues, a good contrast was showed between muscle fibers and other fibrillar connective tissues. Through the observation of the obtained images, we found that most orbicularis oris fibers gathered into bundles with clear outline and only had slight deformation and displacement on the health side of the cleft of the unilateral incomplete cleft lip; however, in the lateral cleft, the muscle fibers not only had deformation and displacement but also were immature, disorganized, and not gathered into bundles. After being restored in Digital Imaging and Communications in Medicine format, the obtained images were then transferred into Materialise's interactive medical image control system, edited, and reconstructed into three-dimensional models. The models clearly showed the spatial relationship between the muscular tissues of the nasolabial region and the nasolabial outline in fetus with cleft lip.

Patched1 is required in neural crest cells for the prevention of orofacial clefts.

Defects such as cleft lip with or without cleft palate (CL/P) are among the most common craniofacial birth defects in humans. In many cases, the underlying molecular and cellular mechanisms that result in these debilitating anomalies remain largely unknown. Perturbed hedgehog (HH) signalling plays a major role in craniofacial development, and mutations in a number of pathway constituents underlie craniofacial disease. In particular, mutations in the gene encoding the major HH receptor and negative regulator, patched1 (PTCH1), are associated with both sporadic and familial forms of clefting, yet relatively little is known about how PTCH1 functions during craniofacial morphogenesis. To address this, we analysed the consequences of conditional loss of Ptch1 in mouse neural crest cell-derived facial mesenchyme. Using scanning electron microscopy (SEM) and live imaging of explanted facial primordia, we captured defective nasal pit invagination and CL in mouse embryos conditionally lacking Ptch1. Our analysis demonstrates interactions between HH and FGF signalling in the development of the upper lip, and reveals cell-autonomous and non-autonomous roles mediated by Ptch1. In particular, we show that deletion of Ptch1 in the facial mesenchyme alters cell morphology, specifically in the invaginating nasal pit epithelium. These findings highlight a critical link between the neural crest cells and olfactory epithelium in directing the morphogenesis of the mammalian lip and nose primordia. Importantly, these interactions are critically dependent on Ptch1 function for the prevention of orofacial clefts.

Transverse nasal crease and transverse nasal milia: clinical variants of the same entity.

BACKGROUND: Transverse nasal crease is an uncommonly reported entity. It likely represents an embryologic fault line. Transverse nasal milia have also been reported in the same location, both as an isolated finding and in a transverse nasal crease. This observation suggests they are variants of the same entity. OBSERVATIONS: Two cases, one of transverse nasal crease with milia and one of transverse nasal milia in the absence of a crease, are reported. A review of the literature on these rarely reported conditions was performed. CONCLUSIONS: It is important for clinicians to be aware of transverse nasal creases, since they may be encountered in a dermatologic practice. Transverse nasal creases, milia in transverse nasal creases, transverse nasal milia, and transverse nasal comedones in the absence of a transverse nasal crease are likely variants of the same entity. They most probably occur because the triangular cartilage and the alar cartilage attach in a linear fashion at the junction of the middle and lower third of the nose. This produces a potential embryonic fault line in which retention cysts presenting as milia and comedones can occur. These clinical presentations merit attention because they are likely much more common than reported.

The effect of facial asymmetry on nasal deviation.

The impact of facial asymmetry on nasal deviation is an accepted but poorly understood part of plastic surgery and rhinology training. Recently, an increased understanding of the specific structural issues underlying this deformity has led to improved surgical techniques and patient outcomes.

Reproductive dysfunction and decreased GnRH neurogenesis in a mouse model of CHARGE syndrome.

CHARGE is a multiple congenital anomaly disorder and a common cause of pubertal defects, olfactory dysfunction, growth delays, deaf-blindness, balance disorders and congenital heart malformations. Mutations in CHD7, the gene encoding chromodomain helicase DNA binding protein 7, are present in 60-80% of individuals with the CHARGE syndrome. Mutations in CHD7 have also been reported in the Kallmann syndrome (olfactory dysfunction, delayed puberty and hypogonadotropic hypogonadism). CHD7 is a positive regulator of neural stem cell proliferation and olfactory sensory neuron formation in the olfactory epithelium, suggesting that the loss of CHD7 might also disrupt development of other neural populations. Here we report that female Chd7(Gt/+) mice have delays in vaginal opening and estrus onset, and erratic estrus cycles. Chd7(Gt/+) mice also have decreased circulating levels of luteinizing hormone and follicle-stimulating hormone but apparently normal responsiveness to gonadotropin-releasing hormone (GnRH) agonist and antagonist treatment. GnRH neurons in the adult Chd7(Gt/+) hypothalamus and embryonic nasal region are diminished, and there is decreased cellular proliferation in the embryonic olfactory placode. Expression levels of GnRH1 and Otx2 in the hypothalamus and GnRHR in the pituitary are significantly reduced in adult Chd7(Gt/+) mice. Additionally, Chd7 mutant embryos have CHD7 dosage-dependent reductions in expression levels of Fgfr1, Bmp4 and Otx2 in the olfactory placode. Together, these data suggest that CHD7 has critical roles in the development and maintenance of GnRH neurons for regulating puberty and reproduction.

Maxilla-nasion-mandible angle: a new method to assess profile anomalies in pregnancy.

OBJECTIVES: To collect normative data and test the feasibility and reproducibility of measurement of the maxilla-nasion-mandible (MNM) angle between 16 and 36 weeks' gestation and its diagnostic ability in a group of pathological cases. METHODS: The MNM angle is defined as the angle between the intersection of the maxilla-nasion and mandible-nasion lines in the exact mid-sagittal plane. After assessing reproducibility, the MNM angle was measured in 3D volumes in 241 fetuses cross-sectionally and in 11 fetuses longitudinally. The MNM angle was then tested in 18 pathological cases with facial malformations or syndromes with specific facial features. RESULTS: The MNM angle could be measured in 92.3% of normal fetuses. Intra- and interobserver intraclass correlation coefficient (ICC) variability was 0.92 and 0.81, respectively. The difference between paired measurements performed by one or two observers was less than 2.5° and 3.6°, respectively in 95% of the cases. The mean MNM angle was 13.5° and did not change significantly during pregnancy (r = - 0.08, P = 0.25). The MNM angle was above the 95(th) centile in all cases of retrognathia and maxillary alveolar ridge interruption. The MNM angle was below the 5(th) centile in Apert syndrome, thanatophoric dysplasia and in two of the three Down syndrome cases. CONCLUSIONS: The feasibility and reproducibility of measurement of the MNM angle is good. The MNM angle can be used to evaluate the convexity of the fetal profile by enabling an objective assessment of the anteroposterior relationship of the jaws and it may therefore be of help in the diagnosis of retrognathia, maxillary alveolar ridge interruption and flat profile.

The supernumerary nostril.

The supernumerary nostril is a very rare congenital nasal abnormality, and several cases have been reported in the literature since 1906 when the first case was reported by Lindsay. In the other previously reported cases, the supernumerary nostril typically could present unilaterally or bilaterally, and it was therefore called a double nose, with most reported cases being unilateral. At our institution, we encountered a patient with a supernumerary nostril that was located above the left nostril. We thus performed an operation on this supernumerary nostril and obtained good results and a successful postoperative course. We herein present our findings while also discussing the pertinent literature.

Supernumerary nostril: a case report and review / Fosa nasal supernumeraria: reporte de un caso y revisión

Supernumerary nostril is a very rare congenital anomaly, which includes additional nostril with or without accessory cartilage. In the present case of the left supernumerary nostril, a small cavity of around 3 mm diameter and accessory lower lateral cartilage were present. The cavity was lined with mucous membrane and filled with mucoid discharge .Nasal endoscopy of accessory nasal cavity revealed that it was small as compared to normal nasal cavity and did not communicate with the ipsilateral nasal cavity. The diameter of the normal anterior nasal opening was less on left side as compared to right side. Unilateral supernumerary nostril may occur because of the Assuring of the lateral nasal process during fetal growth.

Fosa nasal supernumeraria es una anomalía congénita muy poco frecuente, que incluye una nueva fosa nasal con o sin cartílago accesorio. En el presente caso de fosa nasal supernumeraria izquierda estaban presentes, una pequeña cavidad de unos 3 mm de diámetro y cartílago lateral accesorio inferior. La cavidad estaba revestida con membranas mucosas y llena con descarga mucoide. La endoscopía nasal de la cavidad nasal accesoria reveló que ésta era pequeña en comparación con la cavidad nasal normal y que no se comunicaba con la cavidad nasal ipsilateral. El diámetro normal de la apertura nasal anterior fue menor en el lado izquierdo en comparación con el lado derecho. La fosa nasal unilateral supernumeraria puede ocurrir a causa de las fisuras del proceso lateral nasal durante el crecimiento fetal.

The influence of catecholamine on the migration of gonadotropin-releasing hormone-producing neurons in the rat foetuses.

Catecholamines (CA) play an important role in the regulation of GnRH neurons in adults, and it is probable that they control GnRH-neuron development. Migration of GnRH neurons was evaluated in male and female rats at the 17th embryonic day (E17) and E21, following the daily treatment of their pregnant mothers from the 11th to the 16th and 20th day of gestation with alpha-methyl-para-tyrosine (alphaMPT), an inhibitor of catecholamine synthesis. High-performance liquid chromatography with electrochemical detection (HPLC-ED) was used to specify the alphaMPT-induced CA depletion. There was a 50-70% decrease in dopamine and noradrenaline content in the nose and in the brain of alphaMPT-treated foetuses, proving the efficacy of this pharmacological model. Immunohistochemistry was used to evaluate the percentage (%) of GnRH neurons along their migration pathway from the vomeronasal organ (VNO) in the nose to the septo-preoptic area in the forebrain which is considered as an index of neuron migration. Special attention was paid to the topographic relationships of GnRH neurons with catecholaminergic fibres. These were observed in apposition with GnRH neurons in the entrance to the forebrain. In CA-deficient foetuses, the percentage of GnRH neurons located in the rostral regions extending from the VNO to the septum was greater than in controls. However, no statistically significant difference was found in the forebrain which extended from the septum to the retrochiasmatic area. In conclusion, these data suggest that endogenous catecholamines stimulate the GnRH neuron migration in ontogenesis.

Semaphorin 4D regulates gonadotropin hormone-releasing hormone-1 neuronal migration through PlexinB1-Met complex.

In mammals, reproduction is dependent on specific neurons secreting the neuropeptide gonadotropin hormone-releasing hormone-1 (GnRH-1). These cells originate during embryonic development in the olfactory placode and migrate into the forebrain, where they become integral members of the hypothalamic-pituitary-gonadal axis. This migratory process is regulated by a wide range of guidance cues, which allow GnRH-1 cells to travel over long distances to reach their appropriate destinations. The Semaphorin4D (Sema4D) receptor, PlexinB1, is highly expressed in the developing olfactory placode, but its function in this context is still unknown. Here, we demonstrate that PlexinB1-deficient mice exhibit a migratory defect of GnRH-1 neurons, resulting in reduction of this cell population in the adult brain. Moreover, Sema4D promotes directional migration in GnRH-1 cells by coupling PlexinB1 with activation of the Met tyrosine kinase (hepatocyte growth factor receptor). This work identifies a function for PlexinB1 during brain development and provides evidence that Sema4D controls migration of GnRH-1 neurons.

Pearls for aesthetic reconstruction of cleft lip and nose defects.

Mastery of the anatomy and embryology of the normal and cleft upper lip, primary palate, and secondary palate is an essential foundation for grasping techniques in aesthetic reconstruction of cleft lip defects. The surgical goals in repairing cleft lip deformities are to address the deficiencies of the cleft lip defect, restore static and dynamic anatomy, reshape the cleft nasal deformity, and leave a natural-appearing scar that mimics the contours of the philtral components. An additional goal is to improve skeletal alignment and retention of teeth in the vicinity of the alveolar cleft. There are advantages and disadvantages inherit in all repair techniques. However, there are principles that can be universally applied and that will improve the success of most approaches. Certain steps deserve special attention to detail, which provide for enhanced results in lip repair. In addition, the pearls for aesthetic reconstruction of cleft lip and nose defects outlined within this article--attention to scars and surface detail, utilizing the orthopedic forces of the orbicularis pull to achieve improved alveolar alignment, the importance of mucosal detail, and attention to the cleft nasal defect--will help to improve results and reduce secondary defects.