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PubMed1999

Mice lacking link protein develop dwarfism and craniofacial abnormalities.

Link protein (LP), an extracellular matrix protein in cartilage, stabilizes aggregates of aggrecan and hyaluronan, giving cartilage its tensile strength and elasticity. Cartilage provides the template for endochondral ossification and is crucial for determining the length and width of the skeleton. During endochondral bone formation, hypertrophic chondrocytes die and the cartilage is replaced with bone matrix. Here, we have generated targeted mutations in mice in the gene encoding LP (Crtl1). Homozygotes showed defects in cartilage development and delayed bone formation with short limbs and craniofacial anomalies. Most Crtl1(tm1Nid/tm1Nid) mice died shortly after birth due to respiratory failure, but some survived and developed progressive dwarfism and lordosis of the cervical spine. They showed small epiphysis, slightly flared metaphysis of long bones and flattened vertebrae, characteristic of spondyloepiphyseal dysplasias. The cartilage contained significantly reduced aggrecan depositions in the hypertrophic zone, and decreased numbers of prehypertrophic and hypertrophic chondrocytes. Reduced Indian hedgehog (Ihh) expression was observed in prehypertrophic chondrocytes, and apoptosis was inhibited in hypertrophic chondrocytes. These results indicate that LP is important for the formation of proteoglycan aggregates and normal organization of hypertrophic chondrocytes, and suggest that cartilage matrix has a role in chondrocyte differentiation and maturation.

Animals↗
PubMed2002

Craniofacial abnormalities resulting from targeted disruption of the murine Sim2 gene.

Sim2 is a member of the basic helix-loop-helix PAS transcription factor gene family and is evolutionarily related to the Drosophila single-minded gene, a key regulator of central nervous system midline development. In an effort to determine the biological roles of Sim2 in mammalian development, we disrupted the murine Sim2 gene through gene targeting. Mice homozygous for the disrupted allele (Sim2 -/-) exhibit a cleft of the secondary palate and malformations of the tongue and pterygoid processes of the sphenoid bone. These craniofacial malformations are the most probable cause of aerophagia (air swallowing with subsequent accumulation of air in the gastrointestinal tract) and postnatal death exhibited by Sim2 -/- mice. The developing palates of the Sim2 -/- mice are hypocellular, and at embryonic day 14.5 contain excess extracellular matrix component hyaluronan (HA) compared with heterozygotes and homozygous wild-type littermates. HA plays an important role in the regulation and mechanics of palate development. Its premature accumulation in Sim2 -/- animal palates suggests a regulatory role for Sim2 in HA synthesis and in the establishment of craniofacial architecture.

Animals↗
PubMed2004

Craniofacial abnormalities in a murine knock-out model of mucopolysaccharidosis I H: a computed tomography and anatomic study.

The genetic mucopolysaccharidoses are a group of lysosomal storage diseases in which mucopolysaccharides (glycosaminoglycans) accumulate as the result of a malfunction or lack of a lysosomal degradation enzyme. There are currently seven known forms of mucopolysaccharidoses. Type I results from an enzymatic deficiency of alpha-L-iduronidase. There are three subtypes of mucopolysaccharidoses I that are commonly recognized: Hurler syndrome, Hurler-Scheie syndrome, and Scheie syndrome. Of the three subtypes, Hurler syndrome has the most severe clinical picture. Craniofacial anomalies and cognitive impairment are some of the more pronounced features of Hurler syndrome. Hurler syndrome has been described in cats, dogs, mice, and human beings and is inherited as an autosomal recessive trait. The biochemical nature of the disease is preserved across species lines. Clinically, the disease has similar effects in human beings and animals. It has been difficult to reverse the phenotype of the disease even with replacement of the defective alpha-L-iduronidase enzyme. The purpose of this study is to characterize the cranio-facial differences in the murine knock-out model of Hurler syndrome objectively. Twenty-three measurements were taken from computed tomographic scans in a coronal and sagittal plane on 24 black C57/B6 knock-out Hurler syndrome mice. The seven statistically significant measurements are width of the cervical canal, height of the foramen magnum, width between the external auditory canals, width of the skull base at the mandibular condyles, midocular distance, spread of the mandibular condyles, and width of the zygoma at the maxilla. This information now provides researchers with objective data from living Hurler syndrome-affected mice that will allow them to follow therapies directed at improving craniofacial outcomes for any therapy over time.

Animals↗
PubMed1998

[Craniofacial abnormalities in the Charité Virchow Collection].

On 27 June 1899 Rudolf Virchow (1821-1902) inaugurated the Museum of Pathology at the Charité Hospital. The collection comprised 23,500 pathologic-anatomical specimens. Most of the collection was destroyed in World War II. About 2000 samples were saved. Meanwhile the stock has increased to about 9000 objects. The development, contents and structure of the famous Virchow Collection are described with special reference to craniofacial deformities.

Abnormalities, Severe Teratoid↗
PubMed1998

Craniofacial abnormalities in sleep apnoea syndrome.

One hundred and four men with the suspected diagnosis of sleep apnoea syndrome (SAS) not suffering from neuromuscular diseases or acromegaly were examined by X-ray cephalometry. Subjects suffering from bronchial obstruction, laryngeal carcinoma, suspected Treacher Collins syndrome as well as subjects in whom SAS was not verified were excluded. The remaining 81 men were divided into two groups depending upon disease severity as expressed by the mean index of oxygen desaturations per hour (less than 30-group A; more than 30-group B). In group B, the following parameters were significantly altered as compared with group A: dorsocaudal rotation of the mandible, elongation of the soft palate, and an increase of the saddle angle, increase of the angle of the cranial base, the lower gonion angle and the angle of the inclination of the mandible. Differences in the size of the soft palate, the rotation of the mandible and the size of the lower gonion angle can be found not only between healthy and subjects with SAS but also between subjects with mild and severe apnoea.

Cephalometry↗
PubMed2006

Tcof1/Treacle is required for neural crest cell formation and proliferation deficiencies that cause craniofacial abnormalities.

Neural crest cells are a migratory cell population that give rise to the majority of the cartilage, bone, connective tissue, and sensory ganglia in the head. Abnormalities in the formation, proliferation, migration, and differentiation phases of the neural crest cell life cycle can lead to craniofacial malformations, which constitute one-third of all congenital birth defects. Treacher Collins syndrome (TCS) is characterized by hypoplasia of the facial bones, cleft palate, and middle and external ear defects. Although TCS results from autosomal dominant mutations of the gene TCOF1, the mechanistic origins of the abnormalities observed in this condition are unknown, and the function of Treacle, the protein encoded by TCOF1, remains poorly understood. To investigate the developmental basis of TCS we generated a mouse model through germ-line mutation of Tcof1. Haploinsufficiency of Tcof1 leads to a deficiency in migrating neural crest cells, which results in severe craniofacial malformations. We demonstrate that Tcof1/Treacle is required cell-autonomously for the formation and proliferation of neural crest cells. Tcof1/Treacle regulates proliferation by controlling the production of mature ribosomes. Therefore, Tcof1/Treacle is a unique spatiotemporal regulator of ribosome biogenesis, a deficiency that disrupts neural crest cell formation and proliferation, causing the hypoplasia characteristic of TCS craniofacial anomalies.

Animals↗
PubMed1993

[Obstructive sleep apnea syndrome caused by craniofacial abnormalities].

Patients with obstructive sleep apnoea syndrome frequently present distinct changes in the craniofacial skeleton that result in a structural narrowing of the pharynx and promote pharyngeal collapse during sleep. The evaluation of the clinical data of patients with and without craniofacial dysmorphia reveals that mean age, mean Broca index and the number of additional diseases is decreased in patients with craniofacial dysmorphia. Young patients or patients with normal weight and OSAS usually present such skeletal changes. The number of sleep-related breathing disorders and the extent of nocturnal desaturation are also decreased in the group of patients with dysmorphia. The structure of sleep is similarly disturbed in both groups. In most cases patients with severe obstructive sleep apnoea have normal cephalometric data.

Adult↗
PubMed2003

Thymus, kidney and craniofacial abnormalities in Six 1 deficient mice.

Six genes are widely expressed during vertebrate embryogenesis, suggesting that they are implicated in diverse differentiation processes. To determine the functions of the Six1 gene, we constructed Six1-deficient mice by replacing its first exon by the beta-galactosidase gene. We have previously shown that mice lacking Six1 die at birth due to thoracic skeletal defects and severe muscle hypoplasia affecting most of the body muscles. Here, we report that Six1(-/-) neonates also lack a kidney and thymus, as well as displaying a strong disorganisation of craniofacial structures, namely the inner ear, the nasal cavity, the craniofacial skeleton, and the lacrimal and parotid glands. These organ defects can be correlated with Six1 expression in the embryonic primordium structures as revealed by X-Gal staining at different stages of embryogenesis. Thus, the fetal abnormalities of Six1(-/-) mice appear to result from the absence of the Six 1 homeoprotein during early stages of organogenesis. Interestingly, these Six1 defects are very similar to phenotypes caused by mutations of Eya 1, which are responsible for the BOR syndrome in humans. Close comparison of Six1 and Eya 1 deficient mice strongly suggests a functional link between these two factors. Pax gene mutations also lead to comparable phenotypes, suggesting that a regulatory network including the Pax, Six and Eya genes is required for several types of organogenesis in mammals.

Animals↗
PubMed1995

Abnormal craniofacial growth.

Treatment of patients with craniofacial (CF) anomalies necessitates knowledge about normal CF growth and how it deviates in the abnormal state. There are different basic types of CF anomalies and various kinds of aberrations that influence CF development. These factors might help to explain why patients display growth variations. The effect of surgery on subsequent development is significant, but the heterogeneity among patients with regards to the morphology, etiology, and pathogenesis of the anomalies could also explain certain growth results. Roentgencephalometric findings related to CF growth in three different groups of anomalies are discussed.

Cephalometry↗
PubMed2000

Craniofacial abnormalities induced by retinoic acid: a preliminary histological and scanning electron microscopic (SEM) study.

Exogenous retinoic acid has been found to be teratogenic in animals and man. Craniofacial defects induced by retinoic acid have stimulated considerable research interest. The present report deals with scanning electron microscopical observations of the craniofacial region concurrent with histological examination of craniofacial dysmorphism induced in rat embryos following maternal treatment treated with varying dosages of all-trans-retinoic acid (tretinoin). Two groups of pregnant rats were treated with rat embryos exposed to retinoic acid suspended in corn oil (100 mg/kg b.w. on gestational day 11.5 and 50 mg/kg b.w. on gestational day 10, 11 and 12 respectively). A third group was treated with corn oil (vehicle) while a fourth group remained untreated. A wide spectrum of congenital abnormalities, including exophthalmos, microphthalmia and anophthalmia, maxillo-mandibular dysostosis, micrognathia of both maxilla and mandible, cleft palate, subdevelopment of ear lobe, preauricular tags and macroglossia, were observed in the offspring of retinoic acid treated animals. The abnormalities were both time and dosage dependent, and characteristic of Treacher Collins syndrome when retinoic-acid was administered on gestational day 11.5. In contrast, when retinoic acid was administered were on gestational days 10-12, the defects were similar to those seen in the first and second pharyngeal arch syndrome, as well as in the oculo-auriculo-vertebral spectrum. Whereas our data support the hypothesis that all-trans retinoic-acid disturbs growth and differentiation of several embryonic cell types essential for normal craniofacial development, its mechanism of action remains unclear.

Abnormalities, Drug-Induced↗
PubMed1989

Familial distal arthrogryposis with craniofacial abnormalities: a new subtype of type II?

We report on 5 relatives in 3 generations with an apparent new type of distal arthrogryposis. These individuals have manifestations of type I distal arthrogryposis, but in addition, have craniofacial anomalies that include facial asymmetry, hypertelorism, downslanting palpebral fissures, high nasal bridge, malar hypoplasia, micrognathia, highly arched palate, notched chin, and posteriorly angulated ears. Their intelligence is normal. Although these manifestations preclude us from placing this family in the type I (isolated) distal arthrogryposis category, we also are unable to place them in any of the recognized subtypes of type II distal arthrogryposis. Thus, we think this family may have a previously undescribed form of autosomal dominant type II distal arthrogryposis.

Abnormalities, Multiple↗
PubMed1991

Craniofacial abnormalities in mice with X-linked hypophosphatemic genes (Hyp or Gy).

X-Linked hypophosphatemia is the most common cause of metabolic rickets in humans and is characterized by a reduced renal TmP/GFR and hypophosphatemia. Clinically, these changes are associated with growth retardation including attenuated craniofacial growth, femoral and tibial bowing, and radiologic and histomorphometric evidence of rickets and osteomalacia. Similar mutations occur in mice at the Hyp and Gy gene loci. Direct craniometric measurements were made on mouse skulls to investigate the pattern of craniofacial growth differences in the Hyp/+, Hyp/Hyp and Gy/+ genotypes and to compare these to littermate normals in the C57BL/6J mouse strain. There was generalized attenuation in craniofacial growth in all mutants. The heterozygous Hyp and Gy mutants showed similar patterns of craniofacial growth with diminished neurocranial length, viscerocranial length, and mandibular height. The Gy/+ was significantly smaller than the Hyp/+ in neurocranial width. The homozygous Hyp mouse was not affected more severely than the heterozygous Hyp except in overall cranial length, nasal bone length, and mandibular length from mandibular foramen to third molar. In summary, the heterozygous Hyp and Gy mutant mice showed similar patterns of craniofacial growth. The homozygous Hyp mouse was not affected more severely than the heterozygous Hyp except in three of the 15 measured variables. Thus, these data demonstrate the almost complete dominance of the Hyp gene. In contrast, the Gy gene is incompletely dominant. The heterozygous Gy females survive, but the hemizygous Gy males do not, on a C57BL/6J background. This suggests that there is a family of closely linked genes on the X chromosome which, while similar in their effects on phosphate homeostasis, have differing mechanisms of action.

Animals↗
PubMed1990

Obstructive sleep apnea in Apert's and Pfeiffer's syndromes: more than a craniofacial abnormality.

Nine acrocephalosyndactyly type I patients (Apert's syndrome) and three acrocephalosyndactyly type V patients (Pfeiffer's syndrome) were evaluated for the relative importance of upper and lower airway abnormalities in the generation of obstructive sleep apnea. All patients were found to have a combination of upper and lower abnormalities. The influence of lower pathology was greater in the infants, and the influence of upper airway, specifically pharyngeal, was greater in the adults. A comparison between preoperative and postoperative polysomnography revealed little improvement with standard craniofacial advancements. Furthermore, three patients are described who succumbed to pulmonary death despite tracheostomy. Conservative treatment with prone or lateral positioning and medical pulmonary regimens is advocated. Finally, the pathogenesis of this diffuse airway pathology is discussed.

Acrocephalosyndactylia↗