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PubMed2003

ENU large-scale mutagenesis and quantitative trait linkage (QTL) analysis in mice: novel technologies for searching polygenetic determinants of craniofacial abnormalities.

Discrepancies in size and shape of the jaws are the underlying etiology in many orthodontic and orthognathic surgery patients. Genetic factors combined with environmental interactions have been postulated to play a causal or contributory role in these craniofacial abnormalities. Along with the soon-to-be-available complete human and mouse genomic sequence data, mouse mutants have become a valuable tool in the functional mapping of genes involved in the development of human maxillofacial dysmorphologies. We review two powerful methods in such efforts: N-ethyl-N-nitrosourea (ENU) large-scale mutagenesis and quantitative trait linkage (QTL) analysis. The former aims at producing a plethora of novel variants of particular trait(s), and ultimately mapping the point mutations responsible for the appearance of these new traits. In contrast, the latter applies intensive breeding and mapping techniques to identify multiple loci (and, subsequently, genes) contributing to the phenotypic difference between the tested strains. A prerequisite for either approach to studying variations in the traits of interest is the application of effective mouse cephalometric phenotype analysis and rapid DNA mapping techniques. These approaches will produce a wealth of new data on critical genes that influence the size and shape of the human face.

Alkylating Agents↗
PubMed2000

Partial paternal uniparental disomy of chromosome 6 in an infant with neonatal diabetes, macroglossia, and craniofacial abnormalities.

Neonatal diabetes, which can be transient or permanent, is defined as hyperglycemia that presents within the first month of life and requires insulin therapy. Transient neonatal diabetes mellitus has been associated with abnormalities of the paternally inherited copy of chromosome 6, including duplications of a portion of the long arm of chromosome 6 and uniparental disomy, implicating overexpression of an imprinted gene in this disorder. To date, all patients with transient neonatal diabetes mellitus and uniparental disomy have had complete paternal isodisomy. We describe a patient with neonatal diabetes, macroglossia, and craniofacial abnormalities, with partial paternal uniparental disomy of chromosome 6 involving the distal portion of 6q, from 6q24-qter. This observation demonstrates that mitotic recombination of chromosome 6 can also give rise to uniparental disomy and neonatal diabetes, a situation similar to that observed in Beckwith-Wiedemann syndrome, another imprinted disorder. This finding has clinical implications, since somatic mosaicism for uniparental disomy of chromosome 6 should also be considered in patients with transient neonatal diabetes mellitus.

Aneuploidy↗
PubMed1995

Craniofacial abnormalities in homozygous Small eye (Sey/Sey) embryos and newborn mice.

The Small eye (Sey) gene in the mouse is lethal in the homozygous state. It is located on chromosome 2, is a mutation in the Pax-6 gene, and is genetically homologous with the human aniridia 2 (AN2) gene mutation. Numerous studies over the last few years, using genetic and molecular biological approaches, have investigated both the location of the gene as well as its possible mode of action. In the homozygous state, the primary defect appears to be limited to the failure of differentiation of the presumptive lens and nasal placodes. Such mice therefore display a characteristic phenotype; they possess neither eyes nor any nasal derivatives. Their heterozygous (Sey/+) and normal (+/+) littermates may be distinguished before birth only by a detailed examination of their eyes. Few detailed morphological/histological studies have been undertaken to date in the Sey/Sey embryos and newborn, and in the present study we describe a variety of craniofacial abnormalities that have not previously been reported. We observed, with one exception, delayed closure of the palate, and the presence in 80% of mice of an abnormal complement of upper incisor teeth, so that 35% possessed 1 supernumerary tooth while 45% possessed 2 supernumerary teeth. In these mice, a total of either 3 or 4, rather than the normal complement of 2, upper incisor teeth were present. Possibly the most unexpected finding, however, was the presence of a median cartilaginous rod-like structure which protruded between the 2 maxillae to give the Alizarin red S and Alcian blue-stained 'cleared' skulls of the newborn mice a characteristic 'unicorn-like' appearance. While this structure appeared to be a rostral extension of the chondrocranium, its exact derivation is unclear.

Animals↗
PubMed1997

Craniofacial abnormalities in mice carrying a dominant interference mutation in type X collagen.

Type X collagen is a short, non-fibril forming collagen restricted to hypertrophic cartilage, and has been hypothesized to play a role in endochondral ossification. The purpose of the study was to investigate the consequences resulting from the interference of type X collagen function on the growth and development of the craniofacial skeleton through analysis of transgenic mice with a dominant interference mutation for type X collagen. The craniofacial tissues of 21-day-old transgenic mice were examined by: cephalometric and radiographic densitometry analyses, conventional histology, and immunohistochemistry using antibodies specific for either endogenous mouse type X collagen or the transgene product. Genotypically positive mutant mice showed moderate but statistically significant craniofacial skeletal abnormalities, including the underdevelopment of the chondrocranium and mandible, but no cleft palate. Mean radiographic optical densities of the mutant condylar cartilage and the subchondylar areas were 32% less than the corresponding areas of normal mandibles, while mean radiographic optical density measured at the incisor tooth point remained constant. Histologically, transgene-positive mice revealed compressed hypertrophic cartilage zones and reduced trabeculae in both the mandibular condyle and the synchondroses of the chondrocranium. In the normal condyle, mouse type X collagen was localized by the monospecific antibody against a synthetic rat type X collagen NC1 peptide throughout the hypertrophic cartilage layer; in the mutant condyle, immunoreactivity to endogenous type X collagen was only seen sporadically. The truncated type X collagen transgene product, identified with the monoclonal antibody against an epitope within the chick type X collagen NC2 domain, persisted in the lower hypertrophic cartilage layer and the primary spongiosa, rather than being removed by subsequent endochondral ossification. The data suggested that the expression of the chick type X collagen transgene product was strongly associated with the craniofacial skeletal abnormalities that were distinct from other cartilage-related phenotypes.

Animals↗
PubMed1997

Craniofacial abnormalities induced by the ectopic expression of homeobox genes.

In this paper I have tried to bring together work that highlights the role of homeobox genes in generating craniofacial form. I review both normal and disrupted embryogenesis and ask whether mis-expression of the homeobox genes outside their normal domains could be contributing to congenital facial abnormalities arising from either genetic or teratogenic actions. Experimentally generated transgenic mice carrying loss- or gain-of-function mutations in homeobox genes, in combination with their normal expression patterns, have allowed us to compile and test models of embryonic specification based around a Hox/homeobox code. These models form the basis on which the functional questions are considered. There are four major sections covering different experimental approaches designed to ectopically induce homeobox genes in the head. Transgenic mice, where heterologous promoters drive a given Hox gene in the head, have shown that the more posteriorly expressed Hox genes tend to have a significant effect only on the skull bones of mesodermal origin whereas those normally expressed more anteriorly, in the hindbrain and branchial arches, can affect more anterior branchial arch and neural crest-derived structures. Manipulation experiments which can induce homeobox genes in small, localised regions of the facial precursors show clear and dramatic effects of this expression on facial development. Null mutations in predicted repressors of Hox gene expression, however, do not appear to give rise to substantial craniofacial abnormalities. Retinoic acid, on the other hand, is well known for its teratogenic actions and its ability to induce Hox gene expression. Evidence is now accumulating that at least some of its teratogenic actions may be mediated by its regulation of the Hox and other homeobox genes in the head.

Abnormalities, Drug-Induced↗
PubMed1997

[Parent stress in complex craniofacial abnormalities].

The birth of a child with craniofacial disorders creates tremendous stress on the parents' coping resources. In a postal survey 41 mothers and 32 fathers of children with Apert syndrome report stress concerning acceptance problems and low self-confidence. Both, mothers and fathers express a comparable degree of emotional stress. The quality of family relationships reveals as a buffering factor in coping.

Acrocephalosyndactylia↗
PubMed2004

Abnormal craniofacial development and expression patterns of extracellular matrix components in transgenic Del1 mice harboring a deletion mutation in the type II collagen gene.

OBJECTIVE: To analyze the effect of a type II collagen mutation on craniofacial development in transgenic Del1 mice. DESIGN: Samples from homozygous (+/+) and heterozygous (+/-) transgenic Del1 mice harboring mutations in the type II collagen gene as well as non-transgenic (-/-) littermates were collected at days 12.5, 14.5, 16.5 and 18.5 of gestation. The cartilaginous and bony elements of the craniofacial skeleton were analyzed after staining with alcian blue, alizarin red S and von Kossa. The expression patterns of type II, IX and X collagens and aggrecan were analyzed by immunohistochemistry and in situ hybridization. RESULTS: Several abnormalities were observed in the craniofacial skeleton of transgenic Del1 mice. These include an overall retardation of chondrogenesis and osteogenesis in Del1 +/+ mice, and to a lesser extent also in Del1+/- mice. Characteristic findings in Del1 +/+ mice included a reduced anterioposterior length, a smaller size of the mandible, a palatal cleft and a downward bending snout. We also detected retarded ossification of calvarial bones in Del1 +/+ and +/- mice when compared with Del1 -/- mice. A surprising finding was the presence of both type II and X collagens and their mRNAs in the periosteum of the cranial base. CONCLUSION: The present study confirms the important role of type II collagen mutation in craniofacial development and growth. In addition to affecting endochondral ossification, the type II collagen mutation also disturbs intramembranous ossification in the developing craniofacial skeleton.

Animals↗
PubMed2004

Minor physical anomalies in patients with schizophrenia and their parents: prevalence and pattern of craniofacial abnormalities.

The frequency of minor physical anomalies (MPAs) in patients with schizophrenia suggests an early disturbance in the development of the neuroectoderm. To improve the phenotypic delimitation of this disorder, we used a comprehensive scale of MPAs (41 items) in patients with schizophrenia and their first-degree relatives. This scale, adapted from a revised version of the Waldrop Scale (Ismail et al. Minor physical anomalies in schizophrenic patients and their siblings, American Journal of Psychiatry 155, 1998a, 1695-1702), introduced new items assessing facial and limbs asymmetry. The interrater reliability between two examiners was good: intraclass correlation coefficient: 0.68 (0.42-0.92). Patients with schizophrenia (n=40; mean=5.8, S.D.=4) and their non-psychotic parents (n=45; mean=4.7, S.D.=2.8) had significantly more MPAs than healthy comparison subjects (n=42; mean=2.2, S.D.=1.2). A logistical regression model showed the ability of several items to predict group status, including facial asymmetry, cleft palate, hair whorls and abnormal palmar crease. The high prevalence of facial asymmetry in patients with schizophrenia and their first-degree relatives provides new insights into the underlying dysembryogenic processes. This revised scale thus appears to be a useful complementary tool in pathophysiological studies aiming at the identification of developmental factors in schizophrenia.

Abnormalities, Multiple↗
PubMed1997

Humero-spinal dysostosis: report of the fourth case with emphasis on generalized skeletal involvement, abnormal craniofacial features, and mitral valve thickening.

The fourth reported case of humero-spinal dysostosis is notable in that (a) it confirms the unique combination of bifid distal humeri and coronal clefts, (b) involves a third unique feature as being mitral valve thickening. (c) suggests a more generalized involvement of bone in the form of a dysplasia, and (d) raises the possibility of repetitive craniofacial features.

Abnormalities, Multiple↗
PubMed2005

Management of craniofacial abnormalities.

A number of congenital and acquired conditions can affect the skull, face and jaws resulting in a wide range of craniofacial abnormalites that commonly present at birth or in early infancy. This article aims to outline the aetiology, pathogenesis, diagnosis and principles of management of those conditions that commonly present to a craniofacial unit namely the craniosynostoses.

Adolescent↗
PubMed1998

[Contribution of the clinical psychologists to rehabilitation of children with craniofacial abnormalities].

This paper describes the role of the clinical psychologist collaborating in an interdisciplinary rehabilitation team for children with severe congenital craniofacial disorders. This includes: 1. Psychological counseling during the initial period of responding to the traumatic experience of the child's birth; 2. Preparing the child and parents for surgery and hospitalisation; 3. Developmental assessment and counseling in parenting and educational issues; 4. Prevention of social-emotional disorders and psychological support for the long-term adjustment to facial difference.

Adaptation, Psychological↗
PubMed2000

Connexin43 deficiency causes delayed ossification, craniofacial abnormalities, and osteoblast dysfunction.

Connexin(Cx)43 is the major gap junction protein present in osteoblasts. We have shown that overexpression of Cx45 in osteoblasts expressing endogenous Cx43 leads to decreased cell-cell communication (Koval, M., S.T. Geist, E.M. Westphale, A.E. Kemendy, R. Civitelli, E.C. Beyer, and T.H. Steinberg. 1995. J. Cell Biol. 130:987-995) and transcriptional downregulation of several osteoblastic differentiation markers (Lecanda, F., D.A. Towler, K. Ziambaras, S.-L. Cheng, M. Koval, T.H. Steinberg, and R. Civitelli. 1998. Mol. Biol. Cell 9:2249-2258). Here, using the Cx43-null mouse model, we determined whether genetic deficiency of Cx43 affects skeletal development in vivo. Both intramembranous and endochondral ossification of the cranial vault were delayed in the mutant embryos, and cranial bones originating from migratory neural crest cells were also hypoplastic, leaving an open foramen at birth. Cx43-deficient animals also exhibited retarded ossification of the clavicles, ribs, vertebrae, and limbs, demonstrating that skeletal abnormalities are not restricted to a neural crest defect. However, the axial and appendicular skeleton of Cx43-null animals were essentially normal at birth. Cell to cell diffusion of calcein was poor among Cx43-deficient osteoblasts, whose differentiated phenotypic profile and mineralization potential were greatly impaired, compared with wild-type cells. Therefore, in addition to the reported neural crest cell defect, lack of Cx43 also causes a generalized osteoblast dysfunction, leading to delayed mineralization and skull abnormalities. Cell to cell signaling, mediated by Cx43 gap junctions, was critical for normal osteogenesis, craniofacial development, and osteoblastic function.

Animals↗
PubMed2001

Craniofacial abnormalities in Japanese patients with severe obstructive sleep apnoea syndrome.

OBJECTIVE: To clarify that factors besides obesity play an important role in the development of obstructive sleep apnoea syndrome (OSAS) in Japanese patients, we compared craniofacial structures in patients with severe OSAS with those of normal controls. METHODOLOGY: The craniofacial structures of 60 Japanese patients with severe OSAS and 30 normal controls were evaluated using standard cephalometric analysis. Patients were stratified according to body mass index (BMI): non-obese, BMI < 25; moderately obese, BMI = 25-30, severely obese, BMI > 30. RESULTS: The SNA (sella to nasion to subspinale angle) was significantly smaller in the patient groups than in the controls. The SNB (sella to nasion to supramentale angle) and NSBa (cranial base flexure) were significantly smaller in the non-obese and moderately obese patients than in controls. The MP-H (distance from the mandibular plane to the hyoid bone) and the PNS-P (distance from the posterior nasal spine to the tip of the soft palate) were significantly longer in the patient groups than in the controls. The PNS-P was significantly longer in the severely obese patients than in the non-obese patients. CONCLUSIONS: Japanese patients with severe OSAS have enlargement of the soft tissues and palate as well as craniofacial bony structural abnormalities. This is particularly apparent in non-obese patients.

Body Mass Index↗
PubMed2004

The therapeutic potential of stem cells in the treatment of craniofacial abnormalities.

Anomalies associated with the vertebrate head and face account for a third of all reported major birth defects. Of the principle cell populations that participate in formation of the craniofacial complex, the neural crest is central, generating much of the peripheral nervous system and constituting the predominant connective tissue-forming mesenchyme of the facial skeleton. Many craniofacial anomalies are, therefore, largely attributed to defects in neural crest cell development. Neural crest cells exhibit many of the features of stem cells; they are multipotent, remarkably plastic and have a limited capacity for self-renewal. This article will review recent studies that demonstrate the ability of stem cells to generate neural crest cell populations that form appropriate neural crest derivatives in the developing craniofacial complex, and will discuss the potential application for stem cells in the treatment of craniofacial disorders.

Animals↗
PubMed1997

Craniofacial abnormalities associated with congenital fiber type disproportion myopathy.

Congenital Fiber-Type Disproportion myopathy (CFTD) is a relatively rare muscular disorder due to predominance and reduction in size of type 1 fibers, with large type 2 fibers. After a review of the clinical and histopathological aspects of the disease, the present work described craniofacial skeletal and EMG features of a 9-year-old child affected by CFTD. Narrow maxillary arch, incompetent lips, severe skeletal open bite, and EMG evidence of weakness of masticatory muscles, were found in the examined patient. All these findings are fully consistent with previously-reported craniofacial features of patients affected by myotonic disorders (muscular dystrophy), and they may represent important diagnostic signs of a congenital muscular disease.

Child↗
PubMed2001

Craniofacial abnormalities and their relevance for sleep apnoea syndrome aetiopathogenesis in acromegaly.

OBJECTIVE: To explain the effect of craniofacial relations on the development of the sleep apnoea syndrome (SAS) in acromegaly, and to elucidate how the activity of acromegaly affects the severity of SAS. DESIGN: Prospective observational study. METHODS: Cephalometry and sleep ventilation measurements were performed in 26 acromegalic men and in 96 men with SAS. RESULTS: SAS was found in 20 acromegalic men. Compared with non-acromegalic men with SAS, patients with acromegaly and SAS were found to have: enlargement of almost all linear dimensions; increased angle indicating mandibular protrusion; increased difference between maxillary and mandibular protrusion; articular angle decrease; soft palate lengthening; and pharyngeal airway space (PAS) enlargement in the palatal and uvular-tip planes. A comparison of acromegalic men with and without SAS revealed no significant difference in the craniofacial skeleton, although there was a narrowing of the minimal PAS (MinPAS) and of PAS in the uvular-tip plane in patients with SAS. SAS was more frequent in the patients with active acromegaly. MinPAS in the patients with active acromegaly was narrower than in those without disease activity. CONCLUSION: Skeletal abnormalities in acromegalic men with SAS were different from those in SAS patients without acromegaly. Upper airway narrowing due to changes in pharyngeal soft tissues takes a more relevant share in the development of SAS in acromegalic men than skeletal anomalies.

Acromegaly↗
PubMed1994

Elevated blood pressure and craniofacial abnormalities in mice deficient in endothelin-1.

The endothelin-1 (ET-1) gene was disrupted in mouse embryonic stem cells by homologous recombination to generate mice deficient in ET-1. These ET-1-/- homozygous mice die of respiratory failure at birth and have morphological abnormalities of the pharyngeal-arch-derived craniofacial tissues and organs. ET-1+/- heterozygous mice, which produce lower levels of ET-1 than wild-type mice, develop elevated blood pressure. These results suggest that ET-1 is essential for normal mouse development and may also play a physiological role in cardiovascular homeostasis.

Animals↗