Mutation testing in Treacher Collins Syndrome.
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OBJECTIVE: To report on a study where 97 subjects were screened for mutations in the Treacher Collins syndrome (TCS) gene TCOF1. METHOD: Ninety-seven subjects with a clinical diagnosis of TCS were screened for potential mutations in TCOF1, by means of single strand conformation polymorphism (SSCP) analysis. In those subjects where potential mutations were detected, sequence analysis was performed to determine the site and type of mutation present. RESULTS: Thirty-six TCS-specific mutations are reported including 27 deletions, six point mutations, two splice junction mutations, and one insertion/deletion. This brings the total number of mutations reported to date to 105. CONCLUSION: The importance of detection of these mutations is mainly in postnatal diagnosis and genetic counselling. Knowledge of the family specific mutation may also be used in prenatal diagnosis to confirm whether the foetus is affected or not, and give the parents the choice of whether to continue with the pregnancy. (+info)
Moulding of the generate to control open bite during mandibular distraction osteogenesis.
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Distraction osteogenesis of the craniofacial skeleton has become a widely accepted, safe, and effective means of craniofacial reconstructive surgery. Despite excellent results in general, there are still some uncertainties related to the procedure, such as development of an anterior open bite (AOB) during mandibular distraction. The aim of this study was to examine whether 'moulding of the generate', i.e. use of intermaxillary elastics during the active distraction phase is possible to close the mandibular plane angle and open bite. Three subjects, 13- and 15-year-old males and a 7-year-old female, underwent mandibular linear and angular bilateral distraction osteogenesis with moulding of the generate. Lateral cephalograms were obtained before the introduction of elastics and following distraction, once the activation was stopped and the patients were ready for the consolidation phase. Conventional cephalometric measurements were used to assess possible changes in the mandibular plane angle and incisor position. Three different anchorage systems (dental, orthopaedic, and skeletal) were used for placement of the intermaxillary elastics. Cephalometric examination showed that the mandibular plane angle was decreased during active distraction osteogenesis with the introduction of elastics and angulation of the distraction device. Depending on the type of elastic anchorage system, smaller or greater amounts of extrusion of the incisors were noted. Moulding of the generate during active distraction can be performed to reduce the mandibular plane angle and open bite. To prevent unwanted dentoalveolar changes from occurring during elastic traction, skeletal rather than dental fixation of the elastics is recommended. Intrusive mechanics may be incorporated into the orthodontic appliances to balance extrusive force by the moulding elastics. (+info)
Prenatal ultrasound diagnosis of Nager syndrome.
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Nager syndrome, or acrofacial dysostosis, is a rare malformation complex characterized by facial anomalies (external ear abnormalities and micrognathia) and limb defects (radial hypoplasia and absence of the thumb and/or other digits). Since its first description in 1948, more than 80 cases have been reported in the pediatric literature. However, there is only one previous report on the prenatal recognition of the syndrome, which was at 30 weeks of gestation. We report here a further case of Nager syndrome, prospectively diagnosed at 23 weeks of gestation. (+info)
Proteomic analysis of human Nop56p-associated pre-ribosomal ribonucleoprotein complexes. Possible link between Nop56p and the nucleolar protein treacle responsible for Treacher Collins syndrome.
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Nop56p is a component of the box C/D small nucleolar ribonucleoprotein complexes that direct 2'-O-methylation of pre-rRNA during its maturation. Genetic analyses in yeast have shown that Nop56p plays important roles in the early steps of pre-rRNA processing. However, its precise function remains elusive, especially in higher eukaryotes. Here we describe the proteomic characterization of human Nop56p (hNop56p)-associated pre-ribosomal ribonucleoprotein complexes. Mass spectrometric analysis of purified pre-ribosomal ribonucleoprotein complexes identified 61 ribosomal proteins, 16 trans-acting factors probably involved in ribosome biogenesis, and 29 proteins whose function in ribosome biogenesis is unknown. Identification of pre-rRNA species within hNop56p-associated pre-ribosomal ribonucleoprotein complexes, coupled with the known functions of yeast orthologs of the probable trans-acting factors identified in human, demonstrated that hNop56p functions in the early to middle stages of 60 S subunit synthesis in human cells. Interestingly, the nucleolar phosphoprotein treacle, which is responsible for the craniofacial disorder associated with Treacher Collins syndrome, was found to be a constituent of hNop56p-associated pre-rRNP complexes. The association of hNop56p and treacle within the complexes was independent of rRNA integrity, indicating a direct interaction. In addition, the protein compositions of the treacle-associated and hNop56p-associated pre-ribosomal ribonucleoprotein complexes were very similar, suggesting functional similarities between these two complexes with respect to ribosome biogenesis in human cells. (+info)
Parental origin of mutations in sporadic cases of Treacher Collins syndrome.
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In some autosomal dominant conditions, there is a correlation between new mutations and paternal age, with new mutations arising almost exclusively in the male germ line. To test this hypothesis in Treacher Collins syndrome, we analyzed 22 sporadic cases, determining the parental origin of the pathogenic mutation in 10 informative families. Mutations were found to be of both paternal and maternal origin, without a detectable parental age effect, confirming that a paternal age effect is not universal to all autosomal dominant disorders. A discussion on the parental origin of mutations and paternal age effect in other diseases is included. (+info)
Mandibulofacial dysostosis (Treacher Collins syndrome): a case report.
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Mandibulofacial dysostosis, also known as Treacher Collins syndrome, is a rare congenital anomaly that must be identified in infancy to prevent irrevocable developmental impairment. Information is sparse in the current medical literature concerning this rare syndrome. This article reports a case of Treacher Collins syndrome with the presence of a scarring alopecia and acne keloidalis nuchae, which are possibly coincidental symptoms, but have not been previously described clinically in this malady. (+info)
Genetic background has a major effect on the penetrance and severity of craniofacial defects in mice heterozygous for the gene encoding the nucleolar protein Treacle.
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Treacher Collins syndrome (TCS) is a craniofacial disorder that results from mutations in TCOF1, which encodes the nucleolar protein Treacle. The severity of the clinical features exhibits wide variation and includes hypoplasia of the mandible and maxilla, abnormalities of the external ears and middle ear ossicles, and cleft palate. To determine the in vivo function of Treacle, we previously generated Tcof1 heterozygous mice on a mixed C57BL/6 and 129 background. These mice exhibited a lethal phenotype, which included abnormal development of the maxilla, absence of the eyes and nasal passages, and neural tube defects. Here, we show that placing the mutation onto different genetic backgrounds has a major effect on the penetrance and severity of the craniofacial and other defects. The offspring exhibit markedly variable strain-dependent phenotypes that range from extremely severe and lethal in a mixed CBA/Ca and 129 background, to apparently normal and viable in a mixed BALB/c and 129 background. In the former case, in addition to a profoundly severe craniofacial phenotype, CBA-derived heterozygous mice also exhibited delayed ossification of the long bones, rib fusions, and digit anomalies. The results of our studies indicate that factors in the different genetic backgrounds contribute extensively to the Tcof1 phenotype. (+info)
Genotyping in 46 patients with tentative diagnosis of Treacher Collins syndrome revealed unexpected phenotypic variation.
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To define the range of phenotypic expression in Treacher Collins syndrome (TCS; Franceschetti-Klein syndrome), we performed mutation analysis in the TCOF1 gene in 46 patients with tentative diagnosis of TCS and evaluated the clinical data, including a scoring system. A total of 27 coding exons of TCOF1 and adjacent splice junctions were analysed by direct sequencing. In 36 patients with a clinically unequivocal diagnosis of TCS, we detected 28 pathogenic mutations, including 25 novel alterations. No mutation was identified in the remaining eight patients with unequivocal diagnosis of TCS and 10 further patients, in whom the referring diagnosis of TCS was clinically doubtful. There is no overt genotype-phenotype correlation except that conductive deafness is significantly less frequent in patients with mutations in the 3' part of the open reading frame. Inter- and intrafamilial variation is wide. Some mutation carriers, parents of typically affected patients, are so mildly affected that the diagnosis might be overlooked clinically. This suggests that modifying factors are important for phenotypic expression. Based on these findings, minimal diagnostic criteria were defined: downward slanting palpebral fissures and hypoplasia of the zygomatic arch. The difficulties in genetic counselling, especially diagnosis of family members with a mild phenotype, are described. (+info)