Audiological profile in Apert syndrome.
(41/135)Apert syndrome is one of the craniosynostosis syndromes and is commonly associated with conductive hearing loss, but there are contradicting reports regarding the cause. Retrospective analysis of case notes of Apert syndrome patients seen between 1970 and 2003 was therefore undertaken. Seventy case notes were obtained; 59% were males. The incidence of congenital hearing impairment was 3-6%. Almost all had otitis media with effusion, which tends to persist into adulthood. More than 56% developed permanent low frequency conductive hearing loss by 10-20 years of age. (+info)
Abnormalities in cartilage and bone development in the Apert syndrome FGFR2(+/S252W) mouse.
(42/135)Apert syndrome is an autosomal dominant disorder characterized by malformations of the skull, limbs and viscera. Two-thirds of affected individuals have a S252W mutation in fibroblast growth factor receptor 2 (FGFR2). To study the pathogenesis of this condition, we generated a knock-in mouse model with this mutation. The Fgfr2(+/S252W) mutant mice have abnormalities of the skeleton, as well as of other organs including the brain, thymus, lungs, heart and intestines. In the mutant neurocranium, we found a midline sutural defect and craniosynostosis with abnormal osteoblastic proliferation and differentiation. We noted ectopic cartilage at the midline sagittal suture, and cartilage abnormalities in the basicranium, nasal turbinates and trachea. In addition, from the mutant long bones, in vitro cell cultures grown in osteogenic medium revealed chondrocytes, which were absent in the controls. Our results suggest that altered cartilage and bone development play a significant role in the pathogenesis of the Apert syndrome phenotype. (+info)
Saethre-Chotzen syndrome caused by TWIST 1 gene mutations: functional differentiation from Muenke coronal synostosis syndrome.
(43/135)The Saethre-Chotzen syndrome (SCS) is an autosomal dominant craniosynostosis syndrome with uni- or bilateral coronal synostosis and mild limb deformities. It is caused by loss-of-function mutations of the TWIST 1 gene. In an attempt to delineate functional features separating SCS from Muenke's syndrome, we screened patients presenting with coronal suture synostosis for mutations in the TWIST 1 gene, and for the Pro250Arg mutation in FGFR3. Within a total of 124 independent pedigrees, 39 (71 patients) were identified to carry 25 different mutations of TWIST 1 including 14 novel mutations, to which six whole gene deletions were added. The 71 patients were compared with 42 subjects from 24 pedigrees carrying the Pro250Arg mutation in FGFR3 and 65 subjects from 61 pedigrees without a detectable mutation. Classical SCS associated with a TWIST 1 mutation could be separated phenotypically from the Muenke phenotype on the basis of the following features: low-set frontal hairline, gross ptosis of eyelids, subnormal ear length, dilated parietal foramina, interdigital webbing, and hallux valgus or broad great toe with bifid distal phalanx. Functional differences were even more important: intracranial hypertension as a consequence of early progressive multisutural fusion was a significant problem in SCS only, while mental delay and sensorineural hearing loss were associated with the Muenke's syndrome. Contrary to previous reports, SCS patients with complete loss of one TWIST allele showed normal mental development. (+info)
The Wnt-inducible transcription factor Twist1 inhibits chondrogenesis.
(44/135)Wnt signaling is essential for many developmental processes, including skeletogenesis. To investigate the effects of Wnt signaling during skeletogenesis we studied the effects of Wnt on cultured chondrocytic cells and differentiating limb-bud mesenchyme. We showed that Wnt3a strongly repressed chondrogenesis and chondrocyte gene expression. Canonical Wnt signaling was responsible for the repression of differentiation, as evidenced by results showing that inhibition of glycogen synthase kinase 3 or expression of beta-catenin caused similar repression of differentiation. Significantly, we showed that the transcription repressor Twist1 is induced by canonical Wnt signaling. Expression of Twist1 strongly inhibited chondrocyte gene expression and short hairpin RNA knockdown of Twist1 transcript levels caused increased expression of the chondrocyte-specific genes aggrecan and type II collagen. Interestingly, Twist1 interfered with BMP2-induced expression of aggrecan and type II collagen expression and knockdown of Twist1 augmented BMP2-induced aggrecan and type II collagen expression. These data support the conclusions that Twist1 contributes to the repression of chondrogenesis and chondrocyte gene expression resulting from canonical Wnt signaling and that Twist1 interferes with BMP-dependent signaling. (+info)
Three-dimensional analysis of mandibular growth and tooth eruption.
(45/135)Normal and abnormal jaw growth and tooth eruption are topics of great importance for several dental and medical disciplines. Thus far, clinical studies on these topics have used two-dimensional (2D) radiographic techniques. The purpose of the present study was to analyse normal mandibular growth and tooth eruption in three dimensions based on computer tomography (CT) scans, extending the principles of mandibular growth analysis proposed by Bjork in 1969 from two to three dimensions. As longitudinal CT data from normal children are not available (for ethical reasons), CT data from children with Apert syndrome were employed, because it has been shown that the mandible in Apert syndrome is unaffected by the malformation, and these children often have several craniofacial CT scans performed during childhood for planning of cranial and midface surgery and for follow-up after surgery. A total of 49 datasets from ten children with Apert syndrome were available for study. The number of datasets from each individual ranged from three to seven. The first CT scan in each of the ten series was carried out before 1 year of age, and the ages for the 49 scans ranged from 1 week to 14.5 years. The mandible and the teeth were segmented and iso-surfaces generated. Landmarks were placed on the surface of the mandible, along the mandibular canals, the inner contour of the cortical plate at the lower border of the symphysis menti, and on the teeth. Superimposition of the mandibles in the longitudinal series was performed using the symphysis menti and the mandibular canals as suggested by Bjork. The study supported the findings of stability of the symphysis menti and the mandibular canals as seen in profile view previously reported by Bjork & Skieller in 1983. However, the mandibular canals were, actually, relocated laterally during growth. Furthermore, the position of tooth buds remained relatively stable inside the jaw until root formation started. Eruption paths of canines and premolars were vertical, whereas molars erupted in a lingual direction. The 3D method would seem to offer new insight into jaw growth and tooth eruption, but further studies are needed. (+info)
Metopic suture in fetuses with Apert syndrome at 22-27 weeks of gestation.
(46/135)OBJECTIVES: To examine the possible association of skull deformity and the development of the cranial sutures in fetuses with Apert syndrome. METHODS: Three-dimensional (3D) ultrasound was used to examine the metopic and coronal sutures in seven fetuses with Apert syndrome at 22-27 weeks of gestation. The gap between the frontal bones in the transverse plane of the head at the level of the cavum septi pellucidi was measured and compared to findings in 120 anatomically normal fetuses undergoing routine ultrasound examination at 16-32 weeks. RESULTS: In the normal group, the gap between the frontal bones in the metopic suture at the level of the cavum septi pellucidi, decreased significantly with gestation from a mean of 2.2 mm (5th and 95th centiles: 1.5 mm and 2.9 mm) at 16 weeks to 0.9 mm (5th and 95th centiles: 0.3 mm and 1.6 mm) at 32 weeks. In the seven cases with Apert syndrome, two-dimensional ultrasound examination demonstrated the characteristic features of frontal bossing, depressed nasal bridge and bilateral syndactyly. On 3D examination there was complete closure of the coronal suture and a wide gap in the metopic suture (15-23 mm). CONCLUSION: In normal fetuses, cranial bones are believed to grow in response to the centrifugal pressure from the expanding brain and proximity of the dura to the suture is critical in maintaining its patency. In Apert syndrome, the frontal bossing may be a mere consequence of a genetically predetermined premature closure of the coronal suture. Alternatively, there is a genetically predetermined deformation of the brain, which in turn, through differential stretch of the dura in the temporal and frontal regions, causes premature closure of the coronal suture and impaired closure of the metopic suture. (+info)
Inhibition or activation of Apert syndrome FGFR2 (S252W) signaling by specific glycosaminoglycans.
(47/135)Most Apert syndrome patients harbor a single amino acid mutation (S252W) in fibroblast growth factor (FGF) receptor 2 (FGFR2), which leads to abnormal FGF/FGFR2 signaling. Here we show that specific combinations of FGFs and glycosaminoglycans activate both alternative splice forms of the mutant but not of the wild-type FGF receptors. More importantly, 2-O- and N-sulfated heparan sulfate, prepared by a combined chemical and enzymatic synthesis, antagonized the over-activated FGFR2b (S252W) to basal levels at nanomolar concentrations. These studies demonstrated that specific glycosaminoglycans could be useful in treating ligand-dependent FGFR signaling-related diseases, such as Apert syndrome and cancer. (+info)
Apert syndrome: factors involved in the cognitive development.
(48/135)Apert syndrome is characterized by craniosynostosis, symmetric syndactyly and other systemic malformations, with mental retardation usually present. The objective of this study was to correlate brain malformations and timing for surgery with neuropsychological evaluation. We also tried to determine other relevant aspects involved in cognitive development of these patients such as social classification of families and parents education. Eighteen patients with Apert syndrome were studied, whose ages were between 14 and 322 months. Brain abnormalities were observed in 55.6% of them. The intelligence quotient or developmental quotient values observed were between 45 and 108. Mental development was related to the quality of family environment and parents education. Mental development was not correlated to brain malformation or age at time of operation. In conclusion, quality of family environment was the most significant factor directly involved in mental development of patients with Apert syndrome. (+info)