Common craniofacial anomalies: conditions of craniofacial atrophy/hypoplasia and neoplasia

The spectrum of craniofacial malformations includes conditions of congenital and acquired etiology. The conditions of craniofacial atrophy and hypoplasia may arise primarily or secondary to previous therapeutic interventions. The conditions of progressive hemifacial atrophy (Romberg disease) and radiation-induced hypoplasia will be reviewed on the basis of their etiology, pathogenesis, anatomy, and treatment. Approaches to the surgical management of these conditions will be discussed. The craniofacial neoplastic conditions of fibrous dysplasia, neurofibromatosis, and craniofacial tumors will also be reviewed and discussed.     

Neural crest cell survival is dependent on Rho kinase and is required for development of the mid face in mouse embryos

Neural crest cells (NCC) give rise to much of the tissue that forms the vertebrate head and face, including cartilage and bone, cranial ganglia and teeth. In this study we show that conditional expression of a dominant-negative (DN) form of Rho kinase (Rock) in mouse NCC results in severe hypoplasia of the frontonasal processes and first pharyngeal arch, ultimately resulting in reduction of the maxilla and nasal bones and severe craniofacial clefting affecting the nose, palate and lip. These defects resemble frontonasal dysplasia in humans. Disruption of the actin cytoskeleton, which leads to abnormalities in cell-matrix attachment, is seen in the RockDN;Wnt1-cre mutant embryos. This leads to elevated cell death, resulting in NCC deficiency and hypoplastic NCC-derived craniofacial structures. Rock is thus essential for survival of NCC that form the craniofacial region. We propose that reduced NCC numbers in the frontonasal processes and first pharyngeal arch, resulting from exacerbated cell death, may be the common mechanism underlying frontonasal dysplasia.     

Craniofacial features resembling frontonasal dysplasia with a tubulonodular interhemispheric lipoma in the adult 3H1 tuft mouse

Intracranial lipomas are rare, but 45% of them occur along the midline cisterns between the hemispheres and are often associated with corpus callosum hypoplasia and craniofacial defects. They are difficult to detect as they are generally asymptomatic and visible by MRI or by postmortem examination. The exact cause of these interhemispheric lipomas is not known, but they arise from a developmental defect resulting in the maldifferentiation of mesenchymal cells into mesodermal derivatives that are not normally present. We have identified a new mouse mutant called tuft, exhibiting a forebrain, intracranial lipoma with midline craniofacial defects resembling frontonasal dysplasia (FND) that arose spontaneously in our wild-type 3H1 colony. The tuft trait seems to be transmitted in recessive fashion, but approximately 80% less frequent than the expected Mendelian 25%, due to either incomplete penetrance or prenatal lethality. MRI and histologic analysis revealed that the intracranial lipoma occurred between the hemispheres and often protruded through the sagittal suture. We also observed a lesion at the lamina terminalis (LT) that may indicate improper closure of the anterior neuropore. We have mapped the tuft trait to within an 18 cM region on mouse chromosome 10 by microsatellite linkage analysis and identified several candidate genes involved with craniofacial development and cellular differentiation of adipose tissue. Tuft is the only known mouse model for midline craniofacial defects with an intracranial lipoma. Identifying the gene(s) and mutation(s) causing this early developmental defect will help us understand the pathogenesis of FND and related craniofacial disorders.     

Congenital nasal anomalies: a classification scheme

The purpose of this work was to develop a simple yet comprehensive classification scheme dedicated to congenital nasal anomalies. To date, no such classification system has been proposed and widely used. A 22-year retrospective review was performed. Two hundred sixty-one patients with congenital nasal anomalies were identified. From this extensive database, a systematic morphogenic classification system was devised. Congenital nasal deformities were classified into four categories. Type I, hypoplasia and atrophy, represents paucity, atrophy, or underdevelopments of skin, subcutaneous tissue, muscle, cartilage, and/or bone. Type II, hyperplasia and duplications, representing anomalies of excess tissue, ranging from duplications of parts to complete multiples, are categorized here. In the type III category, clefts, the comprehensive and widely utilized Tessier classification of craniofacial clefts is applied. Type IV deformities consist of neoplasms and vascular anomalies. Both benign and malignant neoplasms are found in this category.     

Face off against ROS: Tcof1/Treacle safeguards neuroepithelial cells and progenitor neural crest cells from oxidative stress during craniofacial development

One‐third of all congenital birth defects affect the head and face, and most craniofacial anomalies are considered to arise through defects in the development of cranial neural crest cells. Cranial neural crest cells give rise to the majority of craniofacial bones, cartilages and connective tissues. Therefore, understanding the events that control normal cranial neural crest and subsequent craniofacial development is important for elucidating the pathogenetic mechanisms of craniofacial anomalies and for the exploring potential therapeutic avenues for their prevention. Treacher Collins syndrome (TCS) is a congenital disorder characterized by severe craniofacial anomalies. An animal model of TCS, generated through mutation of Tcof1, the mouse (Mus musculus) homologue of the gene primarily mutated in association with TCS in humans, has recently revealed significant insights into the pathogenesis of TCS. Apoptotic elimination of neuroepithelial cells including neural crest cells is the primary cause of craniofacial defects in Tcof1 mutant embryos. However, our understanding of the mechanisms that induce tissue‐specific apoptosis remains incomplete. In this review, we describe recent advances in our understanding of the pathogenesis TCS. Furthermore, we discuss the role of Tcof1 in normal embryonic development, the correlation between genetic and environmental factors on the severity of craniofacial abnormalities, and the prospect for prenatal prevention of craniofacial anomalies.     

Androgen metabolism in male and female breast tissue

Incubation studies have been carried out using normal breast tissue and breast tissue from patients with gynecomastia, mammary dysplasia and breast carcinoma to determine the pattern of androstenedione metabolism. All tissues formed estrone (E₁) and testosterone (T) in all incubations. Estradiol (E₂) was isolated in incubations of tissue from 1 to 6 patients with mammary dysplasia, 5 of 6 patients with gynecomastia and in all incubations with normal and carcinoma tissue. Estrone formation was lowest in mammary dysplasia and gynecomastia, and higher in apparently normal breast tissue. The greatest E₁ formation was found in incubations with breast carcinoma tissue, although there was considerable variation within this tissue group. Estradiol formation was low in all tissues, with the highest conversion rates in carcinoma tissue. Testosterone formation in carcinoma tissue was greater than in mammary dysplasia or gynecomastia, but similar to apparently normal tissue. These results indicate that breast tissue from different pathological states varies in its capacity to aromatize androstenedione (A) to estrogenic products and to convert it to other androgens. They have also shown that the pattern of metabolism is distinctive for the nature of the pathological abnormality.     

Computer aided morphometric analysis of oral leukoplakia and oral squamous cell carcinoma

We compared the changes in the cells in the basal layer of normal mucosa, oral leukoplakia with dysplasia and different grades of oral squamous cell carcinoma (OSCC) using computer aided image analysis of tissue sections. We investigated three morphometric parameters: nuclear area (NA), cell area (CA) and their ratio (NA:CA). NA and NA:CA ratio showed a statistically significant increase from dysplasia to increasing grades of OSCC. Nuclear size was useful for differentiating normal tissue, potentially malignant leukoplakia and OSCC.     

Use of amaranthus leucocarpus lectin to differentiate cervical dysplasia (CIN)

Alterations in O-glycosylation of proteins in cell surfaces can originate disorder in cellular function, as well as in cell transformation and tumoral differentiation. In this work, we investigate changes in O-glycosylation in cervical intraepithelial dysplasia (CIN) at different stages of differentiation (CIN I, CIN II, and CIN III) using lectins specific for O-glycosidically linked glycans. Twenty cases with CIN I, CIN II, and CIN III dysplasias each, and 20 normal cases were studied by lectin histochemistry and evaluated under optical microscopy. The lectins from Glycine max and Griffonia simplicifolia showed no differences in their recognition pattern among the different CIN stages and normal tissue. Dolichos Biflorus lectin recognized CIN I dysplasia. Lectin from Amaranthus leucocarpus showed increased reactivity in the presence of CIN II dysplasia, compared with CIN I and CIN III. These results suggest that subtle modifications in the O-glycosylation pattern could be considered in diagnosis or prognosis of cervical precancerous stages.     

Mandibuloacral dysplasia: a report of two Egyptian cases

Mandibuloacral dysplasia (MAD) is a rare disorder. Only 35 patients, coming from 22 families, have been reported worldwide. We report on two Egyptian unrelated girls with MAD. The first patient presented at the age of 5 years with acral defect and partial alopecia. The second patient presented at the age of 17 years with progressive micrognathia and loss of subcutaneous fat from the limbs. Physical examination detected the craniofacial, skeletal and cutaneous changes characteristic of MAD. Both patients were short with progeroid facies and loss of subcutaneous fat from the extremities, which fits lipodystrophy type A pattern. Radiological examination revealed delayed closure of cranial sutures, hypoplastic mandible, hypoplastic clavicles, and acroosteolysis. Both patients had normal glucose tolerance, but had fasting and post-prandial hyperinsulinemia, suggestive of insulin resistance. One patient had elevated serum triglycerides and low normal cholesterol levels, while the other patient had normal levels. Serum leptin was normal in both patients. We review the literature on mandibuloacral dysplasia and discuss the differential diagnosis.     

Morphometry of pseudoepitheliomatous hyperplasia: objective comparison to normal and dysplastic oral mucosae

OBJECTIVE: To compare the architectural and morphometric features of pseudoepitheliomatous hyperplasia (PEH) associated with oral granular cell tumors (GCT), normal oral mucosa and oral epithelial dysplasia. STUDY DESIGN: Quantitative comparisons between the diagnostic entities were carried out at the tissue level by estimating the fractal complexity of the epithelial connective tissue interface and at the cellular level by analyzing the morphometric features of algorithmically segmented epithelial cell areas. RESULTS: Casewise multivariate analysis showed that the fractal properties produced a correct discrimination rate of 96.4% between PEH and normal mucosa. Cellular parameters gave a 100% correct discrimination rate between PEH and mild dysplasia. Combining the fractal and cellular properties also showed 100% discrimination between PEH and normal mucosa and between PEH and mild dysplasia. CONCLUSION: The results show that PEH associated with GCT displays quantifiable morphometric features that make it differentiable from normal oral mucosa and oral epithelial dysplasia.     

Facial morphology as determined by anthropometry: keeping it simple

Anthropometry remains an efficient, noninvasive method for describing craniofacial morphology in spite of the appearance of more sophisticated technologies. The major advantage afforded by anthropometry is its technical simplicity, a fact which makes it a readily available tool for evaluating patients, planning facial surgery, or delineating basic features of craniofacial syndromes. Anthropometry lacks the detail of more powerful technologies, but it is better suited for populational studies because of the availability of comparative, normal databases. The standard z-scores produced by such comparisons lend themselves to multivariate analysis. This type of comparative analysis is not yet possible for computerized tomography, three-dimensional imaging, or photogrammetry. To illustrate the utility of this technique an example is cited from an ongoing study of hypohidrotic ectodermal dysplasia (HED) in which anthropometry reveals details of facial morphology overlooked in previous studies. These include the presence of reduced facial height and a striking reduction in the size of the facial features in spite of the fact that facial widths are comparatively normal. Gene carriers show a similar though nonidentical pattern of defects. Like all morphometric approaches, anthropometry has its limitations. Well-designed protocols minimize these limitations by incorporating multiple facial dimensions in the analysis and by emphasizing careful collection of data with standard instruments and methodology.     

From genotype to phenotype: the differential expression of FGF, FGFR, and TGFbeta genes characterizes human cranioskeletal development and reflects clinical presentation in FGFR syndromes.

Mutations in the fibroblast growth factor receptor (FGFR) genes 1, 2, and 3 are causal in a number of craniofacial dysostosis syndromes featuring craniosynostosis with basicranial and midfacial deformity. Great clinical variability is displayed in the pathologic phenotypes encountered. To investigate the influence of developmental genetics on clinical diversity in these syndromes, the expression of several genes implicated in their pathology was studied at sequential stages of normal human embryo-fetal cranial base and facial ossification (n = 6). At 8 weeks of gestation, FGFR1, FGFR2, and FGFR3 are equally expressed throughout the predifferentiated mesenchyme of the cranium, the endochondral skull base, and midfacial mesenchyme. Both clinically significant isoforms of FGFR2, IgIIIa/c and IgIIIa/b, are coexpressed in maxillary and basicranial ossification. By 10 to 13 weeks, FGFR1 and FGFR2 are broadly expressed in epithelia, osteogenic, and chondrogenic cell lineages. FGFR3, however, is maximally expressed in dental epithelia and proliferating chondrocytes of the skull base, but poorly expressed in the osteogenic tissues of the midface. FGF2 and FGF4, but not FGF7, and TGFbeta1 and TGFbeta3 are expressed throughout both osteogenic and chondrogenic tissues in early human craniofacial skeletogenesis. Maximal FGFR expression in the skull base proposes a pivotal role for syndromic growth dysplasia at this site. Paucity of FGFR3 expression in human midfacial development correlates with the relatively benign human mutant FGFR3 midfacial phenotypes. The regulation of FGFR expression in human craniofacial skeletogenesis against background excess ligand and selected cofactors may therefore play a profound role in the pathologic craniofacial development of children bearing FGFR mutations.     

New insights into craniofacial morphogenesis

No region of our anatomy more powerfully conveys our emotions nor elicits more profound reactions when disease or genetic disorders disfigure it than the face. Recent progress has been made towards defining the tissue interactions and molecular mechanisms that control craniofacial morphogenesis. Some insights have come from genetic manipulations and others from tissue recombinations and biochemical approaches, which have revealed the molecular underpinnings of facial morphogenesis. Changes in craniofacial architecture also lie at the heart of evolutionary adaptation, as new studies in fish and fowl attest. Together, these findings reveal much about molecular and tissue interactions behind craniofacial development.     

FGF-10 is decreased in bronchopulmonary dysplasia and suppressed by Toll-like receptor activation

Many extremely preterm infants continue to suffer from bronchopulmonary dysplasia, which results from abnormal saccular-stage lung development. Here, we show that fibroblast growth factor-10 (FGF-10) is required for saccular lung development and reduced in the lung tissue of infants with bronchopulmonary dysplasia. Although exposure to bacteria increases the risk of bronchopulmonary dysplasia, no molecular target has been identified connecting inflammatory stimuli and abnormal lung development. In an experimental mouse model of saccular lung development, activation of Toll-like receptor 2 (TLR2) or Toll-like receptor 4 (TLR4) inhibited FGF-10 expression, leading to abnormal saccular airway morphogenesis. In addition, Toll-mediated FGF-10 inhibition disrupted the normal positioning of myofibroblasts around saccular airways, similar to the mislocalization of myofibroblasts seen in patients with bronchopulmonary dysplasia. Reduced FGF-10 expression may therefore link the innate immune system and impaired lung development in bronchopulmonary dysplasia.     

面部软组织厚度测量及其在面貌复原中的应用

软组织厚度作为颅骨面貌复原的基础, 具有重要的应用价值。本文借助计算机技术对西安地区132例成年人颅面数据样本开展软组织测量、分析及应用研究, 结果表明, 1)通过分析特征点处软组织厚度和面部软组织分布图, 发现面部软组织分布具有一定的规律, 额头区域软组织厚度薄且样本间差异小, 脸颊区域软组织厚且样本间差异大; 2)通过比较不同年龄段男性软组织厚度的均值, 发现20-30岁阶段软组织厚度均值最小, 50-60岁阶段软组织厚度均值其次, 30-40岁阶段软组织厚度均值最大, 但30-40岁和40-50岁两个年龄段的软组织厚度近似; 通过比较不同年龄段女性软组织厚度的均值, 发现20-30岁阶段软组织厚度均值最小, 30-40岁阶段软组织厚度均值其次, 40-50岁阶段的软组织厚度均值最大; 3)特征点处软组织厚度标准差可以反映面貌体态的差异, 因此根据10个脸颊特征点的软组织厚度均值和标准差实现面貌体态分类; 4)根据不同性别、年龄、体态对应的软组织平均厚度, 应用计算机技术实现给定颅骨的三维面貌复原, 复原结果相比于传统手工复原的结果更加科学。     

A phenotype-driven ENU mutagenesis screen identifies novel alleles with functional roles in early mouse craniofacial development

Proper craniofacial development begins during gastrulation and requires the coordinated integration of each germ layer tissue (ectoderm, mesoderm, and endoderm) and its derivatives in concert with the precise regulation of cell proliferation, migration, and differentiation. Neural crest cells, which are derived from ectoderm, are a migratory progenitor cell population that generates most of the cartilage, bone, and connective tissue of the head and face. Neural crest cell development is regulated by a combination of intrinsic cell autonomous signals acquired during their formation, balanced with extrinsic signals from tissues with which the neural crest cells interact during their migration and differentiation. Although craniofacial anomalies are typically attributed to defects in neural crest cell development, the cause may be intrinsic or extrinsic. Therefore, we performed a phenotype-driven ENU mutagenesis screen in mice with the aim of identifying novel alleles in an unbiased manner, that are critically required for early craniofacial development. Here we describe 10 new mutant lines, which exhibit phenotypes affecting frontonasal and pharyngeal arch patterning, neural and vascular development as well as sensory organ morphogenesis. Interestingly, our data imply that neural crest cells and endothelial cells may employ similar developmental programs and be interdependent during early embryogenesis, which collectively is critical for normal craniofacial morphogenesis. Furthermore our novel mutants that model human conditions such as exencephaly, craniorachischisis, DiGeorge, and Velocardiofacial sydnromes could be very useful in furthering our understanding of the complexities of specific human diseases.     

Tissue expansion in the reconstruction of Tessier craniofacial clefts: a series of 17 patients

Tessier craniofacial clefts are among the most surgically challenging examples of craniofacial dysmorphology. These clefts are characterized by hypoplasia of soft-tissue and skeletal elements throughout the three-dimensional extent of the cleft. Whereas bone grafting and craniofacial osteotomies have been successful toward correcting the underlying skeletal abnormalities, the ultimate success of these reconstructions has been limited by the deficiency of skin and soft tissue. This deficiency demands reconstruction ideally with tissue of like texture, consistency, and, especially in the face, color. Craniofacial tissue expansion was used toward reconstructing these facial clefts with like-quality tissue, allowing for tension-free reconstruction after osteotomy and bone grafting. Seventeen patients with Tessier craniofacial clefts underwent preoperative craniofacial soft-tissue expansion in the surgical management of their clefts. Tissue expansion was used in the primary correction of facial clefts in eight patients, with nine patients undergoing expansion before secondary surgery. In this series, tissue expansion has evolved as an important element in overcoming the skin and soft-tissue deficiency associated with these clefts, allowing for tension-free closure and improved aesthetic results in these surgically challenging patients.     

Expression of cyclooxygenase-1 and cyclooxygenase-2 in normal and pathological human oral mucosa

Cyclooxigenase (COX) is the rate-limiting enzyme for the conversion of arachidonic acid (AA) to prostaglandins (PGs). Two isoforms of COX have been identified: COX-1 is constitutively expressed in many cells and is involved in cell homeostasis, angiogenesis and cell-cell signalling; COX-2 is not expressed in normal condition however it is strongly expressed in inflammation. The oral cavity is constantly exposed to physical and chemical trauma that could lead to mucosal reactions such as hyperplasia, dysplasia and cancer. Early diagnosis is the most important issue to address for a positive outcome of oral cancer; therefore it would be useful to identify molecular markers whose expression is associated with the various stages of oral cancer progression. Since COX enzyme has been involved, with different mechanisms, in the development and progression of malignancies we decided to investigate the expression and localization of COX-1 and COX-2 in normal human oral mucosa and three different pathologies (hyperplasia, dysplasia and carcinoma) by immunohistochemistry and RT-PCR. COX-1 mRNA and protein have been detected already in normal oral mucosa and their expression progressively increases from normal samples towards hyperplasia, dysplasia and finally carcinoma. On the contrary, COX-2 is not expressed in the normal tissue, starts to be expressed in hyperplasia, reaches the maximum activation in dysplasia and then starts to be downregulated in carcinoma.