Congenital craniostenosis with syndactyly.

Mutations within or upstream of the basic helix-loop-helix domain of the TWIST gene are specific to Saethre-Chotzen syndrome. (1/135)

Saethre-Chotzen syndrome (ACS III) is an autosomal dominant craniosynostosis syndrome recently ascribed to mutations in the TWIST gene, a basic helix-loop-helix (b-HLH) transcription factor regulating head mesenchyme cell development during cranial neural tube formation in mouse. Studying a series of 22 unrelated ACS III patients, we have found TWIST mutations in 16/22 cases. Interestingly, these mutations consistently involved the b-HLH domain of the protein. Indeed, mutant genotypes included frameshift deletions/insertions, nonsense and missense mutations, either truncating or disrupting the b-HLH motif of the protein. This observation gives additional support to the view that most ACS III cases result from loss-of-function mutations at the TWIST locus. The P250R recurrent FGFR 3 mutation was found in 2/22 cases presenting mild clinical manifestations of the disease but 4/22 cases failed to harbour TWIST or FGFR 3 mutations. Clinical re-examination of patients carrying TWIST mutations failed to reveal correlations between the mutant genotype and severity of the phenotype. Finally, since no TWIST mutations were detected in 40 cases of isolated coronal craniosynostosis, the present study suggests that TWIST mutations are specific to Saethre-Chotzen syndrome.  (+info)

Decreased proliferation and altered differentiation in osteoblasts from genetically and clinically distinct craniosynostotic disorders. (2/135)

Craniosynostoses are a heterogeneous group of disorders characterized by premature fusion of cranial sutures. Mutations in fibroblast growth factor receptors (FGFRs) have been associated with a number of such conditions. Nevertheless, the cellular mechanism(s) involved remain unknown. We analyzed cell proliferation and differentiation in osteoblasts obtained from patients with three genetically and clinically distinct craniosynostoses: Pfeiffer syndrome carrying the FGFR2 C342R substitution, Apert syndrome with FGFR2 P253R change, and a nonsyndromic craniosynostosis without FGFR canonic mutations, as compared with control osteoblasts. Osteoblasts from craniosynostotic patients exhibited a lower proliferation rate than control osteoblasts. P253R and nonsyndromic craniosynostosis osteoblasts showed a marked differentiated phenotype, characterized by high alkaline phosphatase activity, increased mineralization and expression of noncollagenous matrix proteins, associated with high expression and activation of protein kinase Calpha and protein kinase Cepsilon isoenzymes. By contrast, the low proliferation rate of C342R osteoblasts was not associated with a differentiated phenotype. Although they showed higher alkaline phosphatase activity than control, C342R osteoblasts failed to mineralize and expressed low levels of osteopontin and osteonectin and high protein kinase Czeta levels. Stimulation of proliferation and inhibition of differentiation were observed in all cultures on FGF2 treatment. Our results suggest that an anticipated proliferative/differentiative switch, associated with alterations of the FGFR transduction pathways, could be the causative common feature in craniosynostosis and that mutations in distinct FGFR2 domains are associated with an in vitro heterogeneous differentiative phenotype.  (+info)

Fetal craniofacial structure and intracranial morphology in a case of Apert syndrome. (3/135)

Apert syndrome is characterized by craniosynostosis, midfacial hypoplasia and bilateral syndactyly. We document in detail the intrauterine natural history of Apert syndrome by serial sonographic examination. Ultrasound examination of a 19-week fetus revealed an abnormal appearance of the skull. The subsequent examination including transvaginal brain scanning demonstrated a deformed occipital part of the cerebrum and lateral ventricles, frontal bossing, a low nasal bridge and an abnormal appearance of the fetal hands and feet. The distortion of the fetal profile became progressively worse with advancing gestation. Towards the end of pregnancy, anterior prominence of the cerebrum, ventricles and corpus callosum was demonstrated and mild non-progressive ventriculomegaly was seen. The female 3152-g newborn with the typical facial appearance of Apert syndrome, bilateral syndactyly of the fingers and toes and isolated cleft palate was delivered at 37 weeks. Postnatal three-dimensional computed tomography scan demonstrated the fusion of the coronal suture and a wide mid-line calvarial defect, and cranial magnetic resonance imaging confirmed the prenatal sonographic findings. Although the karyotype was normal, genomic DNA analysis of the fibroblast growth factor receptor 2 revealed Ser252Trp, which is specified in the mutational basis of Apert syndrome. The time course of the prenatal findings in this case may help increase understanding of the intrauterine natural history of Apert syndrome.  (+info)

Second-trimester molecular prenatal diagnosis of sporadic Apert syndrome following suspicious ultrasound findings. (4/135)

Apert syndrome, an autosomal dominant disorder characterized by craniosynostosis, mid-facial malformations, symmetric bony syndactyly of hands and feet, and varying degrees of mental retardation, is most frequently caused by a de novo mutation. Two missense mutations in the fibroblast growth factor receptor 2 (FGFR2) gene have been found to account for the disorder in approximately 98% of affected patients. Seven cases of prenatal ultrasound diagnosis have been reported. Although one earlier diagnosis has been made in a familial case, sporadic cases have not been definitively diagnosed until the third trimester when craniosynostosis is usually detected. We report a second-trimester molecular diagnosis of a sporadic case, based on the ultrasound observation of fetal 'mitten hands' and craniosynostosis. We discuss the approach to such ultrasound features, given the current availability of molecular diagnosis for Apert syndrome.  (+info)

Paternal origin of FGFR2 mutations in sporadic cases of Crouzon syndrome and Pfeiffer syndrome. (5/135)

Crouzon syndrome and Pfeiffer syndrome are both autosomal dominant craniosynostotic disorders that can be caused by mutations in the fibroblast growth factor receptor 2 (FGFR2) gene. To determine the parental origin of these FGFR2 mutations, the amplification refractory mutation system (ARMS) was used. ARMS PCR primers were developed to recognize polymorphisms that could distinguish maternal and paternal alleles. A total of 4,374 bases between introns IIIa and 11 of the FGFR2 gene were sequenced and were assayed by heteroduplex analysis, to identify polymorphisms. Two polymorphisms (1333TA/TATA and 2710 C/T) were found and were used with two previously described polymorphisms, to screen a total of 41 families. Twenty-two of these families were shown to be informative (11 for Crouzon syndrome and 11 for Pfeiffer syndrome). Eleven different mutations in the 22 families were detected by either restriction digest or allele-specific oligonucleotide hybridization of ARMS PCR products. We molecularly proved the origin of these different mutations to be paternal for all informative cases analyzed (P=2. 4x10-7; 95% confidence limits 87%-100%). Advanced paternal age was noted for the fathers of patients with Crouzon syndrome or Pfeiffer syndrome, compared with the fathers of control individuals (34. 50+/-7.65 years vs. 30.45+/-1.28 years, P<.01). Our data on advanced paternal age corroborates and extends previous clinical evidence based on statistical analyses as well as additional reports of advanced paternal age associated with paternal origin of three sporadic mutations causing Apert syndrome (FGFR2) and achondroplasia (FGFR3). Our results suggest that older men either have accumulated or are more susceptible to a variety of germline mutations.  (+info)

Integration of FGF and TWIST in calvarial bone and suture development. (6/135)

Mutations in the FGFR1-FGFR3 and TWIST genes are known to cause craniosynostosis, the former by constitutive activation and the latter by haploinsufficiency. Although clinically achieving the same end result, the premature fusion of the calvarial bones, it is not known whether these genes lie in the same or independent pathways during calvarial bone development and later in suture closure. We have previously shown that Fgfr2c is expressed at the osteogenic fronts of the developing calvarial bones and that, when FGF is applied via beads to the osteogenic fronts, suture closure is accelerated (Kim, H.-J., Rice, D. P. C., Kettunen, P. J. and Thesleff, I. (1998) Development 125, 1241-1251). In order to investigate further the role of FGF signalling during mouse calvarial bone and suture development, we have performed detailed expression analysis of the splicing variants of Fgfr1-Fgfr3 and Fgfr4, as well as their potential ligand Fgf2. The IIIc splice variants of Fgfr1-Fgfr3 as well as the IIIb variant of Fgfr2 being expressed by differentiating osteoblasts at the osteogenic fronts (E15). In comparison to Fgf9, Fgf2 showed a more restricted expression pattern being primarily expressed in the sutural mesenchyme between the osteogenic fronts. We also carried out a detailed expression analysis of the helix-loop-helix factors (HLH) Twist and Id1 during calvaria and suture development (E10-P6). Twist and Id1 were expressed by early preosteoblasts, in patterns that overlapped those of the FGF ligands, but as these cells differentiated their expression dramatically decreased. Signalling pathways were further studied in vitro, in E15 mouse calvarial explants. Beads soaked in FGF2 induced Twist and inhibited Bsp, a marker of functioning osteoblasts. Meanwhile, BMP2 upregulated Id1. Id1 is a dominant negative HLH thought to inhibit basic HLH such as Twist. In Drosophila, the FGF receptor FR1 is known to be downstream of Twist. We demonstrated that in Twist(+/)(-) mice, FGFR2 protein expression was altered. We propose a model of osteoblast differentiation integrating Twist and FGF in the same pathway, in which FGF acts both at early and late stages. Disruption of this pathway may lead to craniosynostosis.  (+info)

Signaling by fibroblast growth factors (FGF) and fibroblast growth factor receptor 2 (FGFR2)-activating mutations blocks mineralization and induces apoptosis in osteoblasts. (7/135)

Fibroblast growth factors (FGF) play a critical role in bone growth and development affecting both chondrogenesis and osteogenesis. During the process of intramembranous ossification, which leads to the formation of the flat bones of the skull, unregulated FGF signaling can produce premature suture closure or craniosynostosis and other craniofacial deformities. Indeed, many human craniosynostosis disorders have been linked to activating mutations in FGF receptors (FGFR) 1 and 2, but the precise effects of FGF on the proliferation, maturation and differentiation of the target osteoblastic cells are still unclear. In this report, we studied the effects of FGF treatment on primary murine calvarial osteoblast, and on OB1, a newly established osteoblastic cell line. We show that FGF signaling has a dual effect on osteoblast proliferation and differentiation. FGFs activate the endogenous FGFRs leading to the formation of a Grb2/FRS2/Shp2 complex and activation of MAP kinase. However, immature osteoblasts respond to FGF treatment with increased proliferation, whereas in differentiating cells FGF does not induce DNA synthesis but causes apoptosis. When either primary or OB1 osteoblasts are induced to differentiate, FGF signaling inhibits expression of alkaline phosphatase, and blocks mineralization. To study the effect of craniosynostosis-linked mutations in osteoblasts, we introduced FGFR2 carrying either the C342Y (Crouzon syndrome) or the S252W (Apert syndrome) mutation in OB1 cells. Both mutations inhibited differentiation, while dramatically inducing apoptosis. Furthermore, we could also show that overexpression of FGF2 in transgenic mice leads to increased apoptosis in their calvaria. These data provide the first biochemical analysis of FGF signaling in osteoblasts, and show that FGF can act as a cell death inducer with distinct effects in proliferating and differentiating osteoblasts.  (+info)

A Pro250Arg substitution in mouse Fgfr1 causes increased expression of Cbfa1 and premature fusion of calvarial sutures. (8/135)

Pfeiffer syndrome is a classic form of craniosynostosis that is caused by a proline-->arginine substitution at amino acid 252 (Pro252Arg) in fibroblast growth factor receptor 1 (FGFR1). Here we show that mice carrying a Pro250Arg mutation in Fgfr1, which is orthologous to the Pfeiffer syndrome mutation in humans, exhibit anterio-posteriorly shortened, laterally widened and vertically heightened neurocraniums. Analysis of the posterior and anterior frontal, sagittal and coronal sutures of early post-natal mutant mice revealed premature fusion. The sutures of mutant mice had accelerated osteoblast proliferation and increased expression of genes related to osteoblast differentiation, suggesting that bone formation at the sutures is locally increased in Pfeiffer syndrome. Of note, dramatically increased expression of core-binding transcription factor alpha subunit type 1 (Cbfa1) accompanied premature fusion, suggesting that Cbfa1 may be a downstream target of Fgf/Fgfr1 signals. This was confirmed in vitro, where we demonstrate that transfection with wild-type or mutant Fgfr1 induces Cbfa1 expression. The induced expression was also observed using Fgf ligands (Fgf2 and Fgf8). These studies provide direct genetic evidence that the Pro252Arg mutation in FGFR1 causes human Pfeiffer syndrome and uncovers a molecular mechanism in which Fgf/Fgfr1 signals regulate intramembraneous bone formation by modulating Cbfa1 expression.  (+info)

Acrocephalosyndactyly is a genetic disorder that affects the development of the skull and limbs. The term comes from the Greek words "acros," meaning extremity, "cephale," meaning head, and "syndactylia," meaning webbed or fused fingers or toes.

There are several types of acrocephalosyndactyly, but the most common is Type 1, also known as Apert syndrome. People with Apert syndrome have a characteristic appearance, including a high, prominent forehead (acrocephaly), widely spaced eyes (hypertelorism), and underdeveloped upper jaw and midface (maxillary hypoplasia). They also have webbed or fused fingers and toes (syndactyly) and may have other skeletal abnormalities.

Acrocephalosyndactyly is caused by a mutation in the FGFR2 gene, which provides instructions for making a protein that is involved in the development of bones and tissues. The mutation leads to overactive signaling of the FGFR2 protein, which can cause abnormal bone growth and fusion.

Treatment for acrocephalosyndactyly typically involves a team of specialists, including geneticists, orthopedic surgeons, craniofacial surgeons, and other healthcare professionals. Surgery may be necessary to correct skeletal abnormalities, improve function, and enhance appearance. Speech therapy, occupational therapy, and other supportive care may also be recommended.

Pfeiffer RA (1964). "Dominant erbliche Akrocephalosyndaktylie" [Dominant Hereditary Acrocephalosyndactylia]. Zeitschrift für ... acrocephalosyndactylia) that were inherited in an autosomal dominant pattern. In 1996, a son was born to American musician ...
... acrocephalosyndactylia MeSH C05.116.099.370.894.819 - syndactyly MeSH C05.116.099.370.894.819.100 - acrocephalosyndactylia MeSH ... acrocephalosyndactylia MeSH C05.660.906.819 - syndactyly MeSH C05.660.906.819.100 - acrocephalosyndactylia MeSH C05.660.906.819 ... acrocephalosyndactylia MeSH C05.660.585.800.756 - poland syndrome MeSH C05.660.585.984 - thanatophoric dysplasia MeSH C05.660. ... acrocephalosyndactylia MeSH C05.660.207.410 - holoprosencephaly MeSH C05.660.207.525 - leopard syndrome MeSH C05.660.207.540 - ...
Acrocephalosyndactylia at the U.S. National Library of Medicine Medical Subject Headings (MeSH) v t e v t e (CS1 maint: others ...
... acrocephalosyndactylia MeSH C16.131.621.906.819 - syndactyly MeSH C16.131.621.906.819.100 - acrocephalosyndactylia MeSH C16.131 ... acrocephalosyndactylia MeSH C16.131.621.585.800.756 - Poland syndrome MeSH C16.131.621.585.984 - thanatophoric dysplasia MeSH ... acrocephalosyndactylia MeSH C16.131.621.207.410 - holoprosencephaly MeSH C16.131.621.207.525 - Leopard syndrome MeSH C16.131. ...
... syndrome Congenital syphilis Hydrocephalus Microcephaly Pfeiffer syndrome Saethre-Chotzen syndrome Acrocephalosyndactylia ...
Pfeiffer RA (1964). "Dominant erbliche Akrocephalosyndaktylie" [Dominant Hereditary Acrocephalosyndactylia]. Zeitschrift für ... acrocephalosyndactylia) that were inherited in an autosomal dominant pattern. In 1996, a son was born to American musician ...
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Apert syndrome is named for the French physician who described the syndrome acrocephalosyndactylia in 1906. Apert syndrome is a ... of cases arise by new mutation.The syndrome is named for the French physician who described the syndrome acrocephalosyndactylia ...
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Liao, W., Zheng, Y., Kajita, H., Kishi, K. & Sato, I., 2022, Medical Image Computing and Computer Assisted Intervention - MICCAI 2022 - 25th International Conference, Proceedings. Wang, L., Dou, Q., Fletcher, P. T., Speidel, S. & Li, S. (eds.). Springer Science and Business Media Deutschland GmbH, p. 560-570 11 p. (Lecture Notes in Computer Science (including subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics); vol. 13436 LNCS).. 研究成果: Conference contribution ...
Acrocephalosyndactylia Medicine & Life Sciences 55% * Nose Medicine & Life Sciences 22% * Comorbidity Medicine & Life Sciences ...
Acrocephalosyndactylia Medicine & Life Sciences 100% * Craniosynostoses Medicine & Life Sciences 85% * Second Pregnancy ...
Acrocephalosyndactylia Medicine & Life Sciences 73% * Haploinsufficiency Medicine & Life Sciences 63% * Autosomal Dominant 5 ...
Fibroblast Growth Factors, Acrocephalosyndactylia, Craniosynostoses, Germ-Line Mutation Abstract. Fibroblast growth factor ...
Acrocephalosyndactylia, Adult, Aging, Alleles, Craniofacial Dysostosis, Exons, Fathers, Female, Gene Frequency, Genetic ...
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Acrocephalosyndactylia. *Acrodermatitis chronica atrophicans laboratory findings. *Acrodermatitis chronica atrophicans ...
... that involve multiple sutures are sometimes associated with congenital syndromes such as ACROCEPHALOSYNDACTYLIA; and ... that involve multiple sutures are sometimes associated with congenital syndromes such as ACROCEPHALOSYNDACTYLIA; and ... that involve multiple sutures are sometimes associated with congenital syndromes such as ACROCEPHALOSYNDACTYLIA; and ...
Apert syndrome is named for the French physician who described the syndrome acrocephalosyndactylia in 1906. Apert syndrome is a ... Apert syndrome is named for the French physician who described the syndrome acrocephalosyndactylia in 1906. ...
Acrocephalosyndactylia, Chromosome Mapping, Chromosomes, Human, Pair 6, Cranial Sutures, Genes, Recessive, Genetic Linkage, ...
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acrocephalosyndactylia Alliance Apert syndrome. 101200 Antley-Bixler syndrome without disordered steroidogenesis Alliance ...
Acrocephalosyndactylia C5.660.207.707.249.100 C16.131.621.207.707.249.100 Actinium D1.268.33.33 Actinoid Series Elements D1.268 ...
Acrocephalosyndactylia C5.660.207.707.249.100 C16.131.621.207.707.249.100 Actinium D1.268.33.33 Actinoid Series Elements D1.268 ...
Acrocephalosyndactylia C5.660.207.707.249.100 C16.131.621.207.707.249.100 Actinium D1.268.33.33 Actinoid Series Elements D1.268 ...
Acrocephalosyndactylia C5.660.207.707.249.100 C16.131.621.207.707.249.100 Actinium D1.268.33.33 Actinoid Series Elements D1.268 ...
Acrocephalosyndactylia C5.660.207.707.249.100 C16.131.621.207.707.249.100 Actinium D1.268.33.33 Actinoid Series Elements D1.268 ...
Acrocephalosyndactylia, Adult, Aged, Aging, Amino Acid Substitution, DNA Mutational Analysis, Female, Heterozygote, Humans, ...
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  • It may be associated with other anomalies, like craniofacial anomalies (cleft lip and/or cleft palate, optic atrophy, low set ears, acrocephalosyndactylia and facial bone anomalies), gastrointestinal anomalies, cardiovascular anomalies, skeletal anomalies, genitourinary anomalie. (jpgo.org)
  • Reproductive fitness is low, and more than 98% of cases arise by new mutation.The syndrome is named for the French physician who described the syndrome acrocephalosyndactylia in 1906. (medscape.com)