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At least 397 records · Page 22Linked to original sources
PubMed2006

Trigonocephaly in Muenke syndrome.

Saethre-Chotzen syndrome is caused by mutations in the TWIST gene on chromosome 7p21.2. However, Muenke et al. [(1997); Am J Hum Genet 91: 555-564] described a new subgroup carrying the Pro250Arg mutation in the fibroblast growth factor receptor (FGFR) 3 gene on chromosome 4p16. Uni or bicoronal synostosis appears to be the main clinical finding in both syndromes. We observed trigonocephaly as a new manifestation in Muenke syndrome. As a consequence we advise to routinely perform mutation analysis of the FGFR1, 2, and 3 genes in children with non-syndromic trigonocephaly.

Amino Acid Substitution↗
PubMed2006

Sudden infant death in a patient with FGFR3 P250R mutation.

P250R mutation in the FGFR3 gene also known as Muenke syndrome is associated with coronal craniosynostosis, sensorineural deafness, craniofacial, and digital abnormalities. We report a family with this mutation associated with sudden death in an affected newborn, most probably due to upper airway obstruction.

Adult↗
PubMed2007

Obesity, hypothyroidism, craniosynostosis, cardiac hypertrophy, colitis, and developmental delay: a novel syndrome.

We describe in two brothers an apparently novel syndrome comprising obesity, congenital hypothyroidism, neonatal colitis, cardiac biventricular hypertrophy, craniosynostosis, and developmental delay. The first brother presented with neonatal colitis and congenital hypothyroidism and died at age 5 weeks of fulminant colitis. The second brother presented neonatally with the same condition, but survived and subsequently developed severe obesity, sagittal and coronal synostosis, and developmental delay. Both pregnancies had been complicated by hemolysis, elevated liver enzymes, and low platelets (HELLP syndrome). Exhaustive genetic and metabolic investigations have failed to provide a unifying pathogenesis. This unique combination of manifestations appears to represent a new syndrome with probable autosomal recessive or X-linked recessive inheritance.

Cardiomegaly↗
PubMed2004

Effects of different kinds of cranial deformation on the incidence of wormian bones.

Researchers have debated whether the presence and frequency of wormian bones (sutural bones, supernumerary bones, and ossicles) are attributable to genetic factors, environmental factors, or both. This research examines the effects of many different kinds of cranial deformation on the incidence of wormian bones. A sample of 127 deformed and undeformed crania from New World archaeological sites was examined. An undeformed cranial sample (n=35) was compared to the following cranially deformed groups: 1) occipital, 2) lambdoid, 3) annular, 4) fronto-vertico-occipital, 5) parallelo-fronto-occipital, and 6) sagittal synostosis. Three levels of degree of cultural cranial deformation were qualitatively determined. Type and number of wormian bones along each major suture were recorded for each cranium. Group means were analyzed using Kruskal-Wallis one-way ANOVA statistical tests to test the null hypothesis that cranial deformation does not have an effect on wormian bone incidence. Results indicate that all forms of cranial deformation affect the frequency of some types of wormian bones. In particular, all cranially deformed groups exhibited significantly greater frequencies of lambdoid ossicles. Apical, parieto-mastoid, and occipito-mastoid wormian bones also appeared with greater frequency in some groups of culturally deformed crania. Further, varying degrees of cultural deformation all had more lambdoid wormian bones than the undeformed group. These results suggest that wormian bone development in posteriorly placed sutures may be affected more by environmental forces than are their anteriorly placed counterparts.

Adult↗
PubMed1991

Wryneck in the ancient Hawaiians.

A unique cranial asymmetry previously noted in the skeletal remains from Mokapu, O'ahu, Hawai'i, is described. The anomaly involves an indentation of one or both of the occipital condyles and facial and vault asymmetry. This examination of the asymmetry includes a search for other reported occurrences, a detailed description, and a differential diagnosis. A multiple working hypothesis approach is employed. Comparison of the osseous material with the expected clinical pictures in craniosynostosis, Kleippel-Feil syndrome, primary basilar impression, and torticollis results in the most likely explanation of congenital torticollis. A high rate of occurrence of the anomaly (1.8%) is found in the skeletal remains from the Hawaiian Islands, but it has been documented in only two instances outside Hawai'i. A survey of patients seen at The Shriner's Hospital for Crippled Children does not reveal a high rate of occurrence of torticollis in Hawaiians relative to other ethnic groups.

Craniosynostoses↗
PubMed1994

Brief communication: the skull attributed to Mozart--craniosynostosis or not?

The results of a detailed morphological analysis of the skull attributed to Mozart are presented which refute a recent claim that the skull as well as several of Mozart's portraits show indications of uncomplicated trigonocephaly. These indications according to the present analysis are within the limits of normal variation and derive from retention of part of the long arm of the anterior fontanelle.

Craniosynostoses↗
PubMed2002

Transforming growth factor-beta 3(Tgf-beta3) in a collagen gel delays fusion of the rat posterior interfrontal suture in vivo.

Postnatal expansion of the intramembranous bones of the craniofacial skeleton occurs as bone growth at sutures. Loss of the bone growth site occurs when the suture fails to form, or when the newly formed sutures become ossified, resulting in premature obliteration. Previous experiments demonstrated that removal of dura mater from fetal rat coronal sutures, or neutralizing transforming growth factor-beta 2 (Tgf-beta2) activity using antibodies resulted in premature obliteration of the suture in vitro. Conversely, addition of Tgf-beta3 to coronal sutures in vitro rescued them from osseous obliteration. To examine whether Tgf-beta3 rescues sutures from obliteration in vivo, a collagen gel was used as a vehicle to deliver Tgf-beta3 to the normally fusing rat posterior interfrontal (IF) suture. Surgery was done on postnatal day 9 (P9) rats, in which collagen gels containing 0, 3, or 30 ng Tgf-beta3 were placed above the IF suture, underneath the periosteum for 2 weeks. By P24, 75-100% of animals in control unoperated, sham-operated, and collagen gel-only groups had fused IF sutures. In contrast, 40% of sutures exposed to 3 ng Tgf-beta3 remained open, while sutures exposed to 30 ng Tgf-beta were similar to controls. By immunohistochemistry, sutures rescued from obliteration by Tgf-beta3 had the same Tgf-beta receptor type II (Tbetar-II) distribution as controls. However, Tgf-beta3-treated sutures had altered Tgf-beta2 and Tbetar-I distribution compared to controls.

Animals↗
PubMed2003

Rescue of coronal suture fusion using transforming growth factor-beta 3 (Tgf-beta 3) in rabbits with delayed-onset craniosynostosis.

Craniosynostosis results in cranial deformities and increased intracranial pressure, which pose extensive and recurrent surgical management problems. Developmental studies in rodents have shown that low levels of transforming growth factor-beta 3 (Tgf-beta 3) are associated with normal fusion of the interfrontal (IF) suture, and that Tgf-beta 3 prevents IF suture fusion in a dose-dependent fashion. The present study was designed to test the hypothesis that Tgf-beta 3 can also prevent or "rescue" fusing sutures in a rabbit model with familial craniosynostosis. One hundred coronal sutures from 50 rabbits with delayed-onset, coronal suture synostosis were examined in the present study. The rabbits were divided into five groups of 10 rabbits each: 1) sham controls, 2) bovine serum albumin (BSA, 500 ng) low-dose protein controls, 3) low-dose Tgf-beta 3 (500 ng), 4) high-dose BSA (1,000 ng) controls, and 5) high-dose Tgf-beta 3 (1,000 ng). At 10 days of age, radiopaque amalgam markers were implanted in all of the rabbits on either side of the coronal suture to monitor sutural growth. At 25 days of age, the BSA or Tgf-beta 3 was combined with a slow-absorbing collagen vehicle and injected subperiosteally above the coronal suture. Radiographic results revealed that high-dose Tgf-beta 3 rabbits had significantly greater (P < 0.05) coronal suture marker separation than the other groups. Histomorphometric analysis revealed that high-dose Tgf-beta 3 rabbits also had patent coronal sutures and significantly (P < 0.01) greater sutural widths and areas than the other groups. The results suggest that there is a dose-dependent effect of TGF-beta 3 on suture morphology and area in these rabbits, and that the manipulation of such growth factors may have clinical applications in the treatment of craniosynostosis.

Animals↗
PubMed2005

Brain morphology in nonsyndromic unicoronal craniosynostosis.

Studies of isolated craniosynostosis have shown biomechanical and biochemical influences on the craniofacial phenotype, resulting from both genetic and epigenetic factors. Much less attention has been directed toward the morphology of the brain, despite the interactive nature of the developing skull and developing brain. The aim of this study is to define the morphology of the brain in nonsyndromic unilateral coronal synostosis (UCS) in order to form more complete hypotheses about the cause of craniosynostosis. Landmark coordinate data were collected from 3D magnetic resonance image reconstructions of the brain in a sample of UCS patients and an age-matched morphologically normal cohort. These data were analyzed using Euclidean distance matrix analysis. The results of our study demonstrate that despite the basic similarity of overall shape of the brain and skull in UCS, the effects of craniosynostosis on the brain are not localized to structures immediately adjacent to the fused suture or to the endocranial surface of the skull. Rather, alterations are observed throughout the volume of the brain, with subcortical structures altered in conjunction with cortical changes. These results indicate that the morphological correlates are different for brain and skull and suggest that there is a large degree of independence in the developmental trajectories of the brain and skull.

Age Factors↗
PubMed2003

Roles of FGF receptors in mammalian development and congenital diseases.

Four fibroblast growth factor receptors (FGFR1-4) constitute a family of transmembrane tyrosine kinases that serve as high affinity receptors for at least 22 FGF ligands. Gene targeting in mice has yielded valuable insights into the functions of this important gene family in multiple biological processes. These include mesoderm induction and patterning; cell growth, migration, and differentiation; organ formation and maintenance; neuronal differentiation and survival; wound healing; and malignant transformation. Furthermore, discoveries that mutations in three of the four receptors result in more than a dozen human congenital diseases highlight the importance of these genes in skeletal development. In this review, we will discuss recent progress on the roles of FGF receptors in mammalian development and congenital diseases, with an emphasis on signal transduction pathways.

Animals↗
PubMed2002

Induction of chondrogenesis in neural crest cells by mutant fibroblast growth factor receptors.

Activating mutations in human fibroblast growth factor receptors (FGFR) result in a range of skeletal disorders, including craniosynostosis. Because the cranial bones are largely neural crest derived, the possibility arises that increased FGF signalling may predispose to premature/excessive skeletogenic differentiation in neural crest cells. To test this hypothesis, we expressed wild-type and mutant FGFRs in quail embryonic neural crest cells. Chondrogenesis was consistently induced when mutant FGFR1-K656E or FGFR2-C278F were electroporated in ovo into stage 8 quail premigratory neural crest, followed by in vitro culture without FGF2. Neural crest cells electroporated with wild-type FGFR1 or FGFR2 cDNAs exhibited no chondrogenic differentiation in culture. Cartilage differentiation was accompanied by expression of Sox9, Col2a1, and osteopontin. This closely resembled the response of nonelectroporated neural crest cells to FGF2 in vitro: 10 ng/ml induces chondrogenesis, Sox9, Col2a1, and osteopontin expression, whereas 1 ng/ml FGF2 enhances cell survival and Sox9 and Col2a1 expression, but never induces chondrogenesis or osteopontin expression. Transfection of neural crest cells with mutant FGFRs in vitro, after their emergence from the neural tube, in contrast, produced chondrogenesis at a very low frequency. Hence, mutant FGFRs can induce cartilage differentiation when electroporated into premigratory neural crest cells but this effect is drastically reduced if transfection is carried out after the onset of neural crest migration.

Alkaline Phosphatase↗
PubMed2003

Erk pathway and activator protein 1 play crucial roles in FGF2-stimulated premature cranial suture closure.

Cranial sutures are an important growth center of the cranial bones, and the suture space must be maintained to permit the cranial adjustments needed to accommodate brain growth. Craniosynostosis, characterized by premature suture closure, mainly results from mutations that generate constitutively active fibroblast growth factor (FGF) receptors. FGF signaling, thus, is responsible for the pathogenesis of craniosynostosis. Even though FGF activates many different signaling pathways, the one involved in premature suture closure has not been defined. We observed that placing FGF2-soaked bead on the osteogenic fronts of cultured mouse calvaria accelerates cranial suture closure and strongly induces the expression of osteopontin, an early marker of differentiated osteoblasts. FGF2 treatment also induced fos and jun mRNAs and later increased the nuclear levels of activator protein 1 (AP1). FGF2 stimulates the expression of osteopontin by inducing expression of AP1, which then binds to its response element in the osteopontin promoter. Blocking of the Erk pathway by PD98059 suppressed the AP1 and osteopontin expression stimulated by FGF2. Coincidently, blocking of the Erk pathway also significantly retarded FGF2-accelerated cranial suture closure. Thus, the Erk pathway mediates FGF/FGF receptor-stimulated cranial suture closure, probably by stimulating synthesis of AP1 that then stimulates the differentiation of osteoblasts.

Amino Acid Motifs↗
PubMed2006

Twist1 dimer selection regulates cranial suture patterning and fusion.

Saethre-Chotzen syndrome is associated with haploinsufficiency of the basic-helix-loop-helix (bHLH) transcription factor TWIST1 and is characterized by premature closure of the cranial sutures, termed craniosynostosis; however, the mechanisms underlying this defect are unclear. Twist1 has been shown to play both positive and negative roles in mesenchymal specification and differentiation, and here we show that the activity of Twist1 is dependent on its dimer partner. Twist1 forms both homodimers (T/T) and heterodimers with E2A E proteins (T/E) and the relative level of Twist1 to the HLH inhibitor Id proteins determines which dimer forms. On the basis of the expression patterns of Twist1 and Id1 within the cranial sutures, we hypothesized that Twist1 forms homodimers in the osteogenic fronts and T/E heterodimers in the mid-sutures. In support of this hypothesis, we have found that genes regulated by T/T homodimers, such as FGFR2 and periostin, are expressed in the osteogenic fronts, whereas genes regulated by T/E heterodimers, such as thrombospondin-1, are expressed in the mid-sutures. The ratio between these dimers is altered in the sutures of Twist1+/- mice, favoring an increase in homodimers and an expansion of the osteogenic fronts. Of interest, the T/T to T/E ratio is greater in the coronal versus the sagittal suture, and this finding may contribute to making the coronal suture more susceptible to fusion due to TWIST haploinsufficiency. Importantly, we were able to inhibit suture fusion in Twist1+/- mice by modulating the balance between these dimers toward T/E formation, by either increasing the expression of E2A E12 or by decreasing Id expression. Therefore, we have identified dimer partner selection as an important mediator of Twist1 function and provide a mechanistic understanding of craniosynostosis due to TWIST haploinsufficiency.

Animals↗
PubMed2001

A survey of TWIST for mutations in craniosynostosis reveals a variable length polyglycine tract in asymptomatic individuals.

The human TWIST gene encodes a 202 amino acid transcription factor characterized by a highly conserved basic-helix-loop-helix motif in the C-terminal half, and a less conserved N-terminal half that has binding activity toward the histone acetyltransferase p300. Between these domains is a repeat region of unknown function that encodes the glycine-rich sequence (Gly)5Ala(Gly)5. Heterozygous mutations of TWIST were previously described in Saethre-Chotzen craniosynostosis syndrome [El Ghouzzi et al., 1997; Howard et al., 1997]. During a search for TWIST mutations in patients with craniosynostosis, we identified, in addition to 11 novel and one previously described bona fide mutations, several individuals with rearrangements of the glycine-rich region, involving either deletion of 18 nucleotides or insertion of three, 15, or 21 nucleotides. None of these rearrangements was consistently associated with clinical disease and we conclude that they are at most weakly pathogenic. The glycine stretch may serve as a flexible linker between the functional domains of the TWIST protein, and as such may be subject to reduced evolutionary constraint.

Amino Acid Sequence↗
PubMed2005

Twenty-six novel EFNB1 mutations in familial and sporadic craniofrontonasal syndrome (CFNS).

Craniofrontonasal syndrome (CFNS) is an X-linked disorder characterized by a more severe manifestation in heterozygous females than in hemizygous males. Heterozygous females have craniofrontonasal dysplasia (CFND) and occasionally extracranial manifestations including midline defects and skeletal abnormalities, whereas hemizygous males show no or only mild features such as hypertelorism and rarely show cleft lip or palate. Mutations in the EFNB1 gene in Xq12 are responsible for familial and sporadic CFNS. The EFNB1 gene encodes ephrin-B1, a transmembrane ligand that also exhibits receptor-like effects. We performed mutation analysis in nine unrelated families and 29 sporadic patients with CFNS. DNA sequencing revealed mutations in 33 (86.8%) cases including 26 distinct novel mutations. A recurrent nonsense mutation, c.196C>T/R66X, was detected in one family and four sporadic patients. The majority of mutations (26/33) were located in exons 2 and 3 of the EFNB1 gene encoding the extracellular ephrin domain. The mutation spectrum includes frameshift, nonsense, missense, and splice site mutations, with a predominance of frameshift and nonsense mutations resulting in premature truncation codons. For the first time we describe mutations in exons 4 and 5 of EFNB1. Of particular interest are the frameshift mutations located in the last 25 codons of EFNB1 encoding the carboxyterminal end of ephrin-B1. They result in an extension by 44 residues. These mutations disrupt the intracellular binding sites for Grb4 and PDZ-effector proteins involved in reverse signaling. We conclude that the major causes of familial as well as sporadic CFNS are loss of function mutations in the EFNB1 gene that comprise premature termination or abrogate receptor-ligand interaction, oligomerization, and ephrin-B1 reverse signaling.

Amino Acid Sequence↗
PubMed1996

Increased bone formation and osteoblastic cell phenotype in premature cranial suture ossification (craniosynostosis).

Craniosynostosis is a heterogeneous disorder characterized by premature fusion of the skull bone sutures. To evaluate the pathogenesis of premature cranial suture ossification in craniosynostosis, we have evaluated the histologic indices of bone formation and the characteristics of osteoblastic cells derived from normal and affected cranial sutures in 47 infants and children, aged 3-18 months, with nonsyndromic craniosynostosis. The histomorphometric analysis of normal and fused sutures showed an age-related decline in the extent of endosteal bone surface covered with osteoid and osteoblasts during postnatal suture ossification. Bone formation was 20-50% higher at 3-6 months of age in fused sutures compared with normal sutures in the same patients. Cells derived from normal and fused sutures displayed characteristics of the osteoblast phenotype in culture. Analysis of [3H]thymidine incorporation into DNA from 1-14 days of culture showed an age-related decrease in osteoblastic cell growth in both normal and affected sutures. The proliferation of osteoblastic cells isolated from fused sutures was similar at all ages to that of cells isolated from normal sutures in the same patients. In contrast, alkaline phosphatase activity and osteocalcin production by osteoblastic cells cultured in basal conditions and after stimulation with 1,25-dihydroxyvitamin D (1,25[OH]2D3), were 53-74% higher in fused sutures compared with cells isolated from normal sutures in the same patients. The results indicate that bone formation activity at the suture site is locally increased in craniosynostosis, and this disorder is associated with increased in vitro parameters of osteoblastic cell differentiation, suggesting that an increased maturation of osteoblastic cells at the site of the suture leads to the premature ossification in nonsyndromic craniosynostosis.

Aging↗
PubMed2005

FGF and FGFR signaling in chondrodysplasias and craniosynostosis.

The first experimental mouse model for FGF2 in bone dysplasia was made serendipitously by overexpression of FGF from a constitutive promoter. The results were not widely accepted, rightfully drew skepticism, and were difficult to publish; because of over 2,000 studies published on FGF-2 at the time (1993), only a few reported a role of FGF-2 in bone growth and differentiation. However, mapping of human dwarfisms to mutations of the FGFRs shortly, thereafter, made the case that bone growth and remodeling was a major physiological function for FGF. Subsequent production of numerous transgenic and targeted null mice for several genes in the bone growth and remodeling pathways have marvelously elucidated the role of FGFs and their interactions with other genes. Indeed, studies of the FGF pathway present one of the best success stories for use of experimental genetics in functionally parsing morphogenetic regulatory pathways. What remains largely unresolved is the pleiotropic nature of FGF-2. How does it accelerate growth in one cell then stimulate apoptosis or retard growth for another cell in the same type of tissue? Some of the answers may come through distinguishing the FGF-2 protein isoforms, made from alternative translation start sites, these appear to have substantially different functions. Although we have made substantial progress, there is still much to be learned regarding FGF-2 as a most complex, enigmatic protein. Studies of genetic models in mice and human FGFR mutations have provided strong evidence that FGFRs are important modulators of osteoblast function during membranous bone formation. However, there is some controversy regarding the effects of FGFR signaling in human and murine genetic models. Although significant progress has been made in our understanding of FGFR signaling, several questions remain concerning the signaling pathways involved in osteoblast regulation by activated FGFR. Additionally, little is known about the specific role of FGFR target genes involved in cranial bone formation. These issues need to be addressed in future in in vitro and in vivo approaches to better understand the molecular mechanisms of action of FGFR signaling in osteoblasts that result in anabolic effects in bone formation.

Animals↗