Common craniofacial anomalies: the facial dysostoses

Learning Objectives: After studying this article, the participant should be able to: 1. Understand the etiology and pathogenesis of facial dysostosis syndromes. 2. Recognize and classify common facial dysostoses. 3. Understand the different management plans for the reconstruction of facial dysostoses. The wide spectrum of craniofacial malformations makes classification difficult. A simple classification system allows an overview of the current understanding of the etiology, assessment, and treatment of the most frequently encountered craniofacial anomalies. Facial dysostoses are reviewed on the basis of their diverse etiology, pathogenesis, anatomy, and treatment. Conditions discussed include craniofacial microsomia, Goldenhar syndrome, Treacher Collins syndrome, Nager syndrome, Binder syndrome, and Pierre Robin sequence. Approaches to the surgical management of these conditions are reviewed.     

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.     

Acute upregulation of hedgehog signaling in mice causes differential effects on cranial morphology

Hedgehog (HH) signaling, and particularly signaling by sonic hedgehog (SHH), is implicated in several essential activities during morphogenesis, and its misexpression causes a number of developmental disorders in humans. In particular, a reduced mitogenic response of cerebellar granule cell precursors to SHH signaling in a mouse model for Down syndrome (DS), Ts65Dn, is substantially responsible for reduced cerebellar size. A single treatment of newborn trisomic mice with an agonist of the SHH pathway (SAG) normalizes cerebellar morphology and restores some cognitive deficits, suggesting a possible therapeutic application of SAG for treating the cognitive impairments of DS. Although the beneficial effects on the cerebellum are compelling, inappropriate activation of the HH pathway causes anomalies elsewhere in the head, particularly in the formation and patterning of the craniofacial skeleton. To determine whether an acute treatment of SAG has an effect on craniofacial morphology, we quantitatively analyzed the cranial form of adult euploid and Ts65Dn mice that were injected with either SAG or vehicle at birth. We found significant deformation of adult craniofacial shape in some animals that had received SAG at birth. The most pronounced differences between the treated and untreated mice were in the midline structures of the facial skeleton. The SAG-driven craniofacial dysmorphogenesis was dose-dependent and possibly incompletely penetrant at lower concentrations. Our findings illustrate that activation of HH signaling, even with an acute postnatal stimulation, can lead to localized dysmorphology of the skull by generating modular shape changes in the facial skeleton. These observations have important implications for translating HH-agonist-based treatments for DS.KEY WORDS: Hedgehog signaling, Craniofacial shape, Down syndrome, Geometric morphometrics     

Irreversible effects of retinoic acid pulse on Xenopus jaw morphogenesis: new insight into cranial neural crest specification

Jaws are formed by cephalic neural crest (CNCCs) and mesodermal cells migrating to the first pharyngeal arch (PA1). A complex signaling network involving different PA1 components then establishes the jaw morphogenetic program. To gather insight on this developmental process, in this study, we analyze the teratogenic effects of brief (1–15 min) pulses of low doses of retinoic acid (RA: 0.25–2 µM) or RA agonists administered to early Xenopus laevis (X.l.) embryos. We show that these brief pulses of RA cause permanent craniofacial defects specifically when treatments are performed during a 6‐hr window (developmental stages NF15–NF23) that covers the period of CNCCs maintenance, migration, and specification. Earlier or later treatments have no effect. Similar treatments performed at slightly different developmental stages within this temporal window give rise to different spectra of malformations. The RA‐dependent teratogenic effects observed in Xenopus can be partially rescued by folinic acid. We provide evidence suggesting that in Xenopus, as in the mouse, RA causes craniofacial malformations by perturbing signaling to CNCCs. Differently from the mouse, where RA affects CNCCs only at the end of their migration, in Xenopus, RA has an effect on CNCCs during all the period ranging from their exit from the neural tube until their arrival in the PA1. Our findings provide a conceptual framework to understand the origin of individual facial features and the evolution of different craniofacial morphotypes. Birth Defects Res (Part B) 89:493–503, 2010. © 2010 Wiley‐Liss, Inc.     

The spectrum of median craniofacial dysplasia

Given the multiple permutations in craniofacial malformations, classification of median craniofacial dysplasia or midline Tessier no. 0 to 14 clefts has been difficult and disjointed. In this review, the authors present a summary of normal embryology, prior terminology, and their proposed new classification system. Median craniofacial dysplasia has tissue agenesis and holoprosencephaly at one end (the hypoplasias), frontonasal hyperplasia and excessive tissue (the hyperplasias) at the other end, and abnormal splitting or clefting and normal tissue volume (dysraphia) occupying the middle portion of the spectrum. These three distinct subclassifications have different forms of anomalies within their groups.     

Classification moléculaire des cancers du sein : utilité en clinique

In spite of the progress of treatments and the discovery of targeted therapies, breast cancer remains the leading cause of cancer mortality among women. It is also the first cancer to get benefits from target therapies against hormone receptors and now HER2. The anatomoclinical classification used to optimize the therapeutics is not always accurate and is a cause of overtreatments or of inappropriate treatments. Tumour cells genomic studies have shown the relationship between genomic alterations and the prognosis and the efficacy of treatments. The molecular classification which results from those studies allowed the emergence of numerous diagnostic tests. They use different technologies and different clinical approaches which should allow a better classification in order to be able to propose a personalized therapy. In this review, eight molecular tests are estimated compared to their scientific validation and to their clinical utility. Protein assays are also reviewed as uPA/PAI-1, the only prognostic marker validated with a level of evidence 1.     

NONRANDOM FACTORS IN MODERN HUMAN MORPHOLOGICAL DIVERSIFICATION: A STUDY OF CRANIOFACIAL VARIATION IN SOUTHERN SOUTH AMERICAN POPULATIONS

The causes of craniofacial variation among human populations have been the subject of controversy. In this work, we studied aboriginal populations from southern South America, the last continental region peopled by humans and with a wide range of ecological conditions. Because of these characteristics, southern South America provides a unique opportunity to study the relative importance of random and nonrandom factors in human diversification. Previous craniometric studies recognized remarkable differences among populations from this region, usually resorting to random factors as the main explanation. In contrast, here we suggest, using tests based on quantitative genetic models, that: (1) the rate of craniofacial divergence among these populations is too high and (2) the patterns of variation within and between populations are too different to be explained by genetic drift alone. In addition, the among-sample craniofacial variation is correlated with climate and diet but not with mtDNA variation. We suggest that the influence of nonrandom factors (e.g., plasticity, selection) on human craniofacial diversification in regions with large ecological variation is more important than generally acknowledged and capable to generate large craniofacial divergence in a short period of time. These results bring nonrandom factors into focus for the interpretation of human craniofacial variation.     

A morphogenetic classification of craniofacial malformations

A new classification of malformations of the face and cranium is proposed, based on embryologic studies and observations concerning a great number of patients seen by the authors. First of all, one should distinguish between cerebral craniofacial (with brain and/or eyes involved) and craniofacial malformations. Craniofacial malformations may be characterized by dysostosis and by synostosis. Malformations with dysostosis may be produced by transformation as well as differentiation defects. Synostosis is always caused by a differentiation defect. A new nomenclature is introduced.     

The application of bone morphogenetic proteins to dental tissue engineering

Progress in understanding the role of bone morphogenetic proteins (BMPs) in craniofacial and tooth development, the demonstration of stem cells in dental pulp and accumulating knowledge on biomaterial scaffolds have set the stage for tissue engineering and regenerative therapy of the craniofacial complex. Furthermore, the recent approval by the US Food and Drug Administration (FDA; Rockville, MD, USA) of recombinant human BMPs for accelerating bone fusion in slow-healing fractures indicates that this protein family may prove useful in designing regenerative treatments in dental applications. In the near term, these advances are likely to be applied to endodontics and periodontal surgery; ultimately, they may facilitate approaches to regenerating whole teeth for use in tooth replacement.     

Effects of ethanol on the primitive streak stage mouse embryo

Recent studies of mouse models have suggested that malformations associated with the fetal alcohol syndrome (FAS) are caused by the effects of ethanol on early embryos during gastrulation and neurulation. A study of Xenopus laevis embryos showed that exposure of gastrula stage amphibian embryos to ethanol inhibits migration of the mesodermal cells, causes formation of small neural plates, and subsequently causes hypoplastic craniofacial malformations in tadpoles. We now report effects of ethanol on the primitive streak stage mouse embryos. An ethanol solution (25%) was injected intraperitonealy twice into mice of 6.5-7.0 days of pregnancy at a dose of 0.015 ml/gm of body weight. Histological and morphometric examinations of 7.5-day embryos, 20 hr after the second injection, showed that the epiblast layer was disorganized and shrunk with formation of many blebs. In addition, formation of the mesodermal cell layer was retarded in the ethanol-treated embryos, suggesting that exposure of gastrula stage embryos to ethanol causes similar abnormalities in mouse and Xenopus embryos. These results suggest that the inhibition of the morphogenetic movements during gastrulation may be the primary effect of ethanol in causing major craniofacial malformations of FAS.     

Competence of cranial ectoderm to respond to Fgf signaling suggests a two-step model of otic placode induction

Vertebrate craniofacial sensory organs derive from ectodermal placodes early in development. It has been suggested that all craniofacial placodes arise from a common ectodermal domain adjacent to the anterior neural plate, and a number of genes have been recently identified that mark such a 'pre-placodal' domain. However, the functional significance of this pre-placodal domain is still unclear. In the present study, we show that Fgf signaling is necessary and sufficient to directly induce some, but not all, markers of the otic placode in ectoderm taken from the pre-placodal domain. By contrast, ectoderm from outside this domain is not competent to express otic markers in response to Fgfs. Grafting na?ve ectoderm into the pre-placodal domain causes upregulation of pre-placodal markers within 8 hours, together with the acquisition of competence to respond to Fgf signaling. This suggests a two-step model of craniofacial placode induction in which ectoderm first acquires pre-placodal region identity, and subsequently differentiates into particular craniofacial placodes under the influence of local inducing signals.     

Extracellular metalloproteinases in neural crest development and craniofacial morphogenesis

Abstract

The neural crest (NC) is a population of migratory stem/progenitor cells that is found in early vertebrate embryos. NC cells are induced during gastrulation, and later migrate to multiple destinations and contribute to many types of cells and tissues, such as craniofacial structures, cardiac tissues, pigment cells and the peripheral nervous system. Recently, accumulating evidence suggests that many extracellular metalloproteinases, including matrix metalloproteinases (MMPs), a disintegrin and metalloproteinases (ADAMs), and ADAMs with thrombospondin motifs (ADAMTSs), play important roles in various stages of NC development. Interference with metalloproteinase functions often causes defects in craniofacial structures, as well as in other cells and tissues that are contributed by NC cells, in humans and other vertebrates. In this review, we summarize the current state of the field concerning the roles of these three families of metalloproteinases in NC development and related tissue morphogenesis, with a special emphasis on craniofacial morphogenesis.     

Age differences in craniofacial dimensions among adults from Indian Knoll,Kentucky

Adult craniofacial expansion with aging has recently been documented in a living US white population sample (Israel, '73a, '77). The present study extends these findings to a prehistoric Amerindian skeletal sample from the Indian Knoll, Kentucky site. Sixteen craniofacial dimensions available for 136 adult males were compared in younger (20–34 years) and older (35–50 years) age groups. Of these, six dimensions showed a significant difference between age groups; all significantly different dimensions were larger in the older adult age group. The multivariate (T²) difference between age groups was highly significant. Comparison of results before and after a size standardization indicated that the majority of differences between age groups were associated with an overall size increase, or expansion with aging, and did not represent merely remodeling, or “shape” changes. The pattern of craniofacial change with age appeared generally similar to that observed in the modern US white sample; however, some differences were noted. It is shown that the age trends observed at Indian Knoll are most likely to reflect true craniofacial growth in size among the adult male inhabitants of the site, rather than secular trends or other artifacts of the sampling procedure. The causes for continuing adult craniofacial expansion are unknown, and probably involve a complex interaction of many factors. However, this pattern of change with age among adults does appear to be characteristic of population samples of widely differing genetic and environmental backgrounds.     

The role of primary bone grafting in complex craniomaxillofacial trauma

The role of craniofacial surgical techniques and immediate bone grafting in the management of complex craniofacial trauma has been reviewed. Four hundred and one patients with complex facial injuries have been treated. Two hundred and forty-one primary bone and cartilage grafts have been performed in 66 patients. Complex facial injuries should be managed by direct exposure, reduction, and fixation of all fractures utilizing interfragmentary wiring. Very comminuted or absent bone is replaced by immediate bone grafting, producing a stable skeleton without the need for external fixation devices. Associated mandibular fractures are managed with rigid internal fixation utilizing A-O technique. Results of immediate bone grafting have been excellent, and complications are rare. All deformities should be corrected, whenever possible, during the initial operation. This one-stage reconstruction of even the most complex facial injuries will prevent severe postoperative traumatic deformity and disability that may be extremely difficult or impossible to correct secondarily.     

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.     

THE DIFFERENTIAL DIAGNOSIS OF RHEUMATISM—A Clinical Study of 500 Cases

Five hundred consecutive admissions to the rheumatism service of a large hospital were reviewed in an effort to establish criteria for accurate differential diagnosis in rheumatic disorders. Forty-one per cent of the patients presented evidence of articular involvement or arthritis; 28 per cent had non-articular rheumatism, embracing the various types of fibrositis; 7 per cent had musculoskeletal neuroses, and 24 per cent had a variety of diseases unrelated to the musculoskeletal system. A working classification of the various causes of musculoskeletal pain is presented and criteria for the differentiation of the individual diseases are suggested.     

The differential diagnosis of rheumatism; a clinical study of 500 cases

Five hundred consecutive admissions to the rheumatism service of a large hospital were reviewed in an effort to establish criteria for accurate differential diagnosis in rheumatic disorders. Forty-one per cent of the patients presented evidence of articular involvement or arthritis; 28 per cent had non-articular rheumatism, embracing the various types of fibrositis; 7 per cent had musculoskeletal neuroses, and 24 per cent had a variety of diseases unrelated to the musculoskeletal system. A working classification of the various causes of musculoskeletal pain is presented and criteria for the differentiation of the individual diseases are suggested.     

On the manipulation and editing of phytosociological and ecological data

Editing and other manipulations of phytosociological data are considered parts of a more comprehensive data management program. The topic is reviewed against the background of an increasing number of presentations in Vegetatio. It is observed that the newer editing programs do not add anything new to the already existing battery of programs. Yet, there is a need for further discussions of some risks in data manipulations, notably a priori deletion of relevés and species transformation of field scores, and incorporation of suitable devices in the packages available. Also, the evaluation of classification results and the allocation of new material to existing classification systems need more attention. So do the problems concerning the production of structured phytosociological tables, as outcomes of multivariate data treatments.     

Morphological differentiation of aboriginal human populations from Tierra del Fuego (Patagonia): implications for South American peopling

This study aims to integrate the craniofacial morphological variation of southern South American populations with the results of mtDNA haplogroup variation, to discuss the South America peopling. Because the causes of morphological differentiation of Fueguian populations are still a controversial subject, the comparison with neutral variation could contribute to elucidate them. Samples of human remains from South America regions were used to analyze the evolutionary relationships. Several craniofacial traits observed in frontal and lateral view were analyzed by means of geometric morphometrics techniques, and the evolutionary relationships based on morphological and molecular data were established in base to ordination analyses. The results from the facial skeleton agree with those obtained from mtDNA haplogroup frequencies, with La Pampa/Chaco samples detached from the Patagonian samples. Hence, the same mechanism that accounts for the pattern of frequency of haplogroups could explain the variation found in facial skeleton among the samples. It is suggested that such geographic pattern of craniofacial and molecular diversity may reflect the effect of genetic drift that occurred in the small founding populations isolated by distance or geographic barriers. Conversely, the results obtained using the traits from the lateral view slightly differ from the molecular results, showing differences between southernmost Patagonian and the other samples. Therefore, mechanisms other than genetic drift (e.g., natural selection) could have acted to shape the pattern observed in some craniofacial structures present in the lateral view, characterized by the fact that the southernmost Patagonian samples display the most robust and dolichocephalic crania.