The Experts below are selected from a list of 1014 Experts worldwide ranked by ideXlab platform
Ethylin Wang Jabs - One of the best experts on this subject based on the ideXlab platform.
-
C-type natriuretic peptide analog treatment of craniosynostosis in a Crouzon Syndrome mouse model
2018Co-Authors: Greg Holmes, Lening Zhang, Joshua Rivera, Ryan Murphy, Claudia Assouline, Lorraine Sullivan, Todd Oppeneer, Ethylin Wang JabsAbstract:Activating mutations of fibroblast growth factor receptors (FGFRs) are a major cause of skeletal dysplasias, and thus they are potential targets for pharmaceutical intervention. BMN 111, a C-type natriuretic peptide analog, inhibits FGFR signaling at the level of the RAF1 kinase through natriuretic peptide receptor 2 (NPR2) and has been shown to lengthen the long bones and improve skull morphology in the Fgfr3Y367C/+ thanatophoric dysplasia mouse model. Here we report the effects of BMN 111 in treating craniosynostosis and aberrant skull morphology in the Fgfr2cC342Y/+ Crouzon Syndrome mouse model. We first demonstrated that NPR2 is expressed in the murine coronal suture and spheno-occipital synchondrosis in the newborn period. We then gave Fgfr2cC342Y/+ and Fgfr2c+/+ (WT) mice once-daily injections of either vehicle or reported therapeutic levels of BMN 111 between post-natal days 3 and 31. Changes in skeletal morphology, including suture patency, skull dimensions, and long bone length, were assessed by micro-computed tomography. Although BMN 111 treatment significantly increased long bone growth in both WT and mutant mice, skull dimensions and suture patency generally were not significantly affected. A small but significant increase in the relative length of the anterior cranial base was observed. Our results indicate that the differential effects of BMN 111 in treating various skeletal dysplasias may depend on the process of bone formation targeted (endochondral or intramembranous), the specific FGFR mutated, and/or the specific signaling pathway changes due to a given mutation.
-
subtle radiographic findings of achondroplasia in patients with Crouzon Syndrome with acanthosis nigricans due to an ala391glu substitution in fgfr3
American Journal of Medical Genetics, 2001Co-Authors: Daniela N Schweitzer, Kelly A Przylepa, John M. Graham, Ethylin Wang Jabs, Ralph S Lachman, Kazuki Okajima, Alan L ShanskeAbstract:A unique type of craniofacial dysostosis, Crouzon Syndrome with acanthosis nigricans (CAN), has been attributed to a specific substitution (Ala391Glu) in the fibroblast growth factor receptor 3 (FGFR3) gene. At birth, individuals with this disorder have craniosynostosis, ocular proptosis, midface hypoplasia, choanal atresia, hydrocephalus, and they experience the onset of acanthosis nigricans during childhood. We report three cases and compare the clinical characteristics of our cases with the previously reported cases of this disorder. Since the Ala391Glu substitution in FGFR3 is close to the substitutions in the transmembrane domain that result in achondroplasia, we carefully reviewed the skeletal findings in six patients. We identified subtle radiographic findings of achondroplasia in all six cases including narrow sacrosciatic notches, short vertebral bodies, lack of the normal increase in interpediculate distance from the upper lumbar vertebrae caudally, and broad, short metacarpals and phalanges. Even before acanthosis nigricans appears, the presence of choanal atresia and hydrocephalus in an individual with features of Crouzon Syndrome should suggest the diagnosis of CAN, and subtle skeletal findings can lend further support to this diagnosis.
-
subtle radiographic findings of achondroplasia in patients with Crouzon Syndrome with acanthosis nigricans due to an ala391glu substitution in fgfr3
American Journal of Medical Genetics, 2001Co-Authors: Daniela N Schweitzer, Kelly A Przylepa, John M. Graham, Ethylin Wang Jabs, Ralph S Lachman, Kazuki Okajima, Alan L ShanskeAbstract:A unique type of craniofacial dysostosis, Crouzon Syndrome with acanthosis nigricans (CAN), has been attributed to a specific substitution (Ala391Glu) in the fibroblast growth factor receptor 3 (FGFR3) gene. At birth, individuals with this disorder have craniosynostosis, ocular proptosis, midface hypoplasia, choanal atresia, hydrocephalus, and they experience the onset of acanthosis nigricans during childhood. We report three cases and compare the clinical characteristics of our cases with the previously reported cases of this disorder. Since the Ala391Glu substitution in FGFR3 is close to the substitutions in the transmembrane domain that result in achondroplasia, we carefully reviewed the skeletal findings in six patients. We identified subtle radiographic findings of achondroplasia in all six cases including narrow sacrosciatic notches, short vertebral bodies, lack of the normal increase in interpediculate distance from the upper lumbar vertebrae caudally, and broad, short metacarpals and phalanges. Even before acanthosis nigricans appears, the presence of choanal atresia and hydrocephalus in an individual with features of Crouzon Syndrome should suggest the diagnosis of CAN, and subtle skeletal findings can lend further support to this diagnosis. © 2001 Wiley-Liss, Inc.
-
fibroblast growth factor receptor 3 fgfr3 transmembrane mutation in Crouzon Syndrome with acanthosis nigricans
Nature Genetics, 1995Co-Authors: Gregory A Meyers, Kelly A Przylepa, Seth J Orlow, Ian R Munro, Ethylin Wang JabsAbstract:Crouzon Syndrome, an autosomal dominant condition characterized by craniosynostosis, ocular proptosis and midface hypoplasia, is associated with mutations in fibroblast growth factor receptor 2 (FGFR2) (refs 1–3). For example, we have identified 10 different mutations in the FGFR2 extracellular immunoglobulin III (Iglll) domain in 50% (16/32) of our Crouzon Syndrome patients2,4,5. All mutations described so far for other craniosynos-totic Syndromes with associated limb anomalies — Jackson–Weiss2,4, Pfeiffer6–9, and Apert10,11 — also occur in the extracellular domain of FGFR2, as well as FGFR1 for Pfeiffer Syndrome. In contrast, only FGFR3 mutations have been reported in dwarfing conditions — achondroplasia12–14, thanatophoric dyspla-sia15,16, and hypochondroplasia17. For achondroplasia, greater than 99% of mutations occur in the FGFR3 transmembrane domain12–14,18,19. We now report the unexpected observation of a FGFR3 transmembrane domain mutation, Ala391Glu, in three unrelated families with Crouzon Syndrome and acanthosis nigricans, a specific skin disorder of hyperkeratosis and hyperpigmentation. The association of non–dwarfing and even non–skeletal conditions with FGFR3 mutations reveals the potential for a wide range of FGFR pleiotropic effects as well as locus heterogeneity in Crouzon Syndrome. Our study underscores the biologic complexity of the FGFR gene family.
-
novel fgfr2 mutations in Crouzon and jackson weiss Syndromes show allelic heterogeneity and phenotypic variability
Human Molecular Genetics, 1995Co-Authors: Woo Jin Park, Gregory A Meyers, X Li, Christiane Theda, Seth J Oriow, Marilyn C Jones, Ethylin Wang JabsAbstract:Mutations have been reported for several craniosynostotic disorders in exon IIIa (exon U or 7) or Illc (exon B or 9) of the fibroblast growth factor receptor 2 gene (FGFR2). Among the conditions with FGFR2 mutations are two autosomal dominant Syndromes, Crouzon and Jackson-Weiss. In this study, 24 Crouzon and one Jackson-Weiss Syndrome patients were screened for mutations in the two exons by direct sequencing, and mutations were detected in 28% (7/25) of all cases. Five different mutations were found including two novel (W290G, C342W) and two previously reported, recurrent mutations for Crouzon Syndrome (A344A, S354C), and one new mutation for Jackson-Weiss Syndrome (C342R). The W290G mutation was found in exon IIIa which is common to both alternatively spliced forms of FGFR2, BEK (expressed predominantly in primordial bones) and KGFR (expressed preferentially in epithelia). Atypical Crouzon Syndrome features of epithelial-derived anal and/or external ear anomalies were present in the two affected family members with the mutation. This phenotype possibly reflects the expression of both mutant BEK and KGFR. In addition, the Jackson-Weiss Syndrome mutation, C342R, in exon Illc was observed previously in other craniosynostotic Syndromes, Crouzon and Pfeiffer. These results underscore the allelic heterogeneity of these conditions and the complexity of the phenotypic consequences of FGFR2 mutations.
Andrew O M Wilkie - One of the best experts on this subject based on the ideXlab platform.
-
germline and somatic mosaicism for fgfr2 mutation in the mother of a child with Crouzon Syndrome implications for genetic testing in paternal age effect Syndromes
American Journal of Medical Genetics Part A, 2010Co-Authors: Anne Goriely, Andrew O M Wilkie, Helen Lord, Jasmine Lim, David Johnson, Tracy Lester, Helen V FirthAbstract:Crouzon Syndrome is a dominantly inherited disorder characterized by craniosynostosis and facial dysostosis, caused by mutations in the fibroblast growth factor receptor 2 (FGFR2) gene; it belongs to a class of disorders that mostly arise as de novo mutations and exhibit a near-exclusive paternal origin of mutation and elevated paternal age ("paternal age effect"). However, even if this is the major mode of origin of mutations in paternal age-effect disorders, germline mosaicism may also occur. Here we describe the first molecularly documented evidence of germline and somatic mosaicism for FGFR2 mutation, identified in the mother of a child with Crouzon Syndrome caused by a heterozygous c.1007A>G (p.Asp336Gly) substitution. Levels of maternal somatic mosaicism for this mutation, estimated by pyrosequencing, ranged from 3.3% in hair roots to 14.1% in blood. Our observation underlines the importance of parental molecular testing for accurate genetic counseling of the risk of recurrence for Crouzon, and other paternal age-effect Syndromes.
-
mutations in the third immunoglobulin domain of the fibroblast growth factor receptor 2 gene in Crouzon Syndrome
Human Molecular Genetics, 1995Co-Authors: Michael Oldridge, Andrew O M Wilkie, Sarah F Slaney, M D Poole, Louise J Pulleyn, Paul Rutland, Anthony D Hockley, M J Wake, J H Goldin, R M WinterAbstract:Craniosynostosis, which affects approximately 1 in 2000 children, is the result of the abnormal development and/or premature fusion of the cranial sutures. Studies of mutations in patients with craniosynostosis have shown that the family of fibroblast growth factor receptor genes are extremely important in the correct formation of the skull, and digits. Mutations in the third immunoglobulin domain of fibroblast growth factor receptor 2 (FGFR2), in part of the molecule corresponding to a tissue specific isoform (IIIc), can cause both Crouzon and Pfeiffer Syndromes. Two specific mutations in the linking region between the second and third immunoglobulin domains of FGFR2 occur in Apert Syndrome. We present here mutations associated with the Crouzon Syndrome, also in the third immunoglobulin domain but in an upstream exon. This exon is expressed in both tissue isoforms. Five different mutations were detected in 11 unrelated individuals. A cysteine to phenylalanine change was found in six individuals. This cysteine forms half of the disulphide bridge maintaining the secondary structure of the immunoglobulin domain. The first deletion within an FGFR gene is reported. Together with mutations in exon IIIc these account for 25 mutations out of 40 Crouzon patients studied in our combined series (5).
-
Apert Syndrome results from localized mutations of FGFR2 and is allelic with Crouzon Syndrome
Nature Genetics, 1995Co-Authors: Andrew O M Wilkie, David J. David, Richard D. Hayward, Michael Oldridge, Sarah F Slaney, Louise J Pulleyn, Anthony D Hockley, Michael D. Poole, Geraldine J. Ashworth, Paul RutlandAbstract:Apert Syndrome is a distinctive human malformation comprising craniosynostosis and severe syndactyly of the hands and feet. We have identified specific missense substitutions involving adjacent amino acids (Ser252Trp and Pro253Arg) in the linker between the second and third extracellular immunoglobulin (Ig) domains of fibroblast growth factor receptor 2 (FGFR2) in all 40 unrelated cases of Apert Syndrome studied. Crouzon Syndrome, characterized by craniosynostosis but normal limbs, was previously shown to result from allelic mutations of the third Ig domain of FGFR2. The contrasting effects of these mutations provide a genetic resource for dissecting the complex effects of signal transduction through FGFRs in cranial and limb morphogenesis.
R M Winter - One of the best experts on this subject based on the ideXlab platform.
-
a recurrent mutation ala391glu in the transmembrane region of fgfr3 causes Crouzon Syndrome and acanthosis nigricans
Journal of Medical Genetics, 1996Co-Authors: D Wilkes, Louise J Pulleyn, Paul Rutland, R M Winter, W Reardon, C Moss, J P Ellis, S MalcolmAbstract:Mutations in the fibroblast growth factor receptor 2 (FGFR2) gene have previously been identified in Crouzon Syndrome, an autosomal dominant condition involving premature fusion of the cranial sutures. Several different missense and other mutations have been identified in Crouzon Syndrome patients, clustering around the third immunoglobulin-like domain. We report here the identification of a mutation in the transmembrane region of FGFR3, common to three unrelated patients with classical Crouzon Syndrome and acanthosis nigricans, a dermatological condition associated with thickening and abnormal pigmentation of the skin. The mutation within the FGFR3 transcript was determined by direct sequencing as a specific gcg to gag transversion, resulting in an amino acid substitution ala391glu within the transmembrane region.
-
mutations in the third immunoglobulin domain of the fibroblast growth factor receptor 2 gene in Crouzon Syndrome
Human Molecular Genetics, 1995Co-Authors: Michael Oldridge, Andrew O M Wilkie, Sarah F Slaney, M D Poole, Louise J Pulleyn, Paul Rutland, Anthony D Hockley, M J Wake, J H Goldin, R M WinterAbstract:Craniosynostosis, which affects approximately 1 in 2000 children, is the result of the abnormal development and/or premature fusion of the cranial sutures. Studies of mutations in patients with craniosynostosis have shown that the family of fibroblast growth factor receptor genes are extremely important in the correct formation of the skull, and digits. Mutations in the third immunoglobulin domain of fibroblast growth factor receptor 2 (FGFR2), in part of the molecule corresponding to a tissue specific isoform (IIIc), can cause both Crouzon and Pfeiffer Syndromes. Two specific mutations in the linking region between the second and third immunoglobulin domains of FGFR2 occur in Apert Syndrome. We present here mutations associated with the Crouzon Syndrome, also in the third immunoglobulin domain but in an upstream exon. This exon is expressed in both tissue isoforms. Five different mutations were detected in 11 unrelated individuals. A cysteine to phenylalanine change was found in six individuals. This cysteine forms half of the disulphide bridge maintaining the secondary structure of the immunoglobulin domain. The first deletion within an FGFR gene is reported. Together with mutations in exon IIIc these account for 25 mutations out of 40 Crouzon patients studied in our combined series (5).
Irene M. J. Mathijssen - One of the best experts on this subject based on the ideXlab platform.
-
the effect of early fusion of the spheno occipital synchondrosis on midface hypoplasia and obstructive sleep apnea in patients with Crouzon Syndrome
Journal of Cranio-maxillofacial Surgery, 2017Co-Authors: Caroline Driessen, Priya N Doerga, Marjolein H G Dremmen, Koen F M Joosten, Bianca F M Rijken, Irene M. J. MathijssenAbstract:Abstract Introduction The investigators hypothesized that patients with Crouzon Syndrome and premature fusion of the spheno-occipital synchondrosis (SOS) more often have, or have more severe midface hypoplasia and obstructive sleep apnea (OSA). Methods A prospective cohort study was performed among patients with Crouzon Syndrome to analyze SOS closure, midface hypoplasia represented by the sella-nasion angle (SNA) and OSA. Results Forty patients were included in whom the OSA-prevalence was 65%. Kaplan Meier analyses suggest a trend towards earlier closure of synchondrosis in patients with OSA (p = 0.066). The mean SNA was 74.7°. There was a positive effect of age on the SNA (p = 0.020). There was no difference in SNA for patients with an open SOS as compared to patients with a closed SOS after correction for age. Conclusions The longitudinal data are suggestive of a trend towards earlier fusion of the SOS in patients with Crouzon Syndrome and OSA as compared to patients with Crouzon Syndrome without OSA. Although the SNA increases with age, our results suggest that this increase in independent closure of the SOS.
-
foramen magnum size and involvement of its intraoccipital synchondroses in Crouzon Syndrome
Plastic and Reconstructive Surgery, 2013Co-Authors: Bianca F M Rijken, Maarten H Lequin, Johan De Rooi, Marie-lise C. Van Veelen, Irene M. J. MathijssenAbstract:textabstractBACKGROUND: Cranial sutures and synchondroses tend to close prematurely in patients with Crouzon Syndrome. This influences their skull vault and skull base development and may involve in common disturbances such as increased intracranial pressure and cerebellar tonsillar herniation. The authors' hypothesis was that Crouzon patients patients have a smaller foramen magnum than controls because of premature fusion of the intraoccipital synchondroses, putting them at risk for cerebellar tonsillar herniation. Therefore, foramen magnum size and time of intraoccipital synchondroses closure were evaluated and were related to the presence and degree of cerebellar tonsillar herniation. METHODS: The foramen magnum surface area and anteroposterior diameter were measured on three-dimensional computed tomographic scans of 27 Crouzon patients and 27 age-matched controls. Scans had a slice-thickness between 0.75 and 1.25 mm and were aligned in a three-dimensional reformatting platform. The t test was used to study size differences. Synchondroses were graded as described by Madeline and Elster and studied with ordinal logistic regression analysis. RESULTS: Crouzon patients had a smaller foramen magnum surface area (602 mm versus 767 mm, p < 0.001) and anteroposterior diameter (31 mm versus 35 mm, p < 0.001) compared with controls. Differences stayed constant over time. Intraoccipital synchondroses closed 3 to 9 months earlier in Crouzon patients than in controls (p < 0.05). CONCLUSIONS: Since intraoccipital synchondroses close earlier in Crouzon patients, from early life on their foramen magnum is smaller compared with controls. Within Crouzon patients, the presence of cerebellar tonsillar herniation could not be related to foramen magnum size. Copyright
Paul Rutland - One of the best experts on this subject based on the ideXlab platform.
-
a recurrent mutation ala391glu in the transmembrane region of fgfr3 causes Crouzon Syndrome and acanthosis nigricans
Journal of Medical Genetics, 1996Co-Authors: D Wilkes, Louise J Pulleyn, Paul Rutland, R M Winter, W Reardon, C Moss, J P Ellis, S MalcolmAbstract:Mutations in the fibroblast growth factor receptor 2 (FGFR2) gene have previously been identified in Crouzon Syndrome, an autosomal dominant condition involving premature fusion of the cranial sutures. Several different missense and other mutations have been identified in Crouzon Syndrome patients, clustering around the third immunoglobulin-like domain. We report here the identification of a mutation in the transmembrane region of FGFR3, common to three unrelated patients with classical Crouzon Syndrome and acanthosis nigricans, a dermatological condition associated with thickening and abnormal pigmentation of the skin. The mutation within the FGFR3 transcript was determined by direct sequencing as a specific gcg to gag transversion, resulting in an amino acid substitution ala391glu within the transmembrane region.
-
mutations in the third immunoglobulin domain of the fibroblast growth factor receptor 2 gene in Crouzon Syndrome
Human Molecular Genetics, 1995Co-Authors: Michael Oldridge, Andrew O M Wilkie, Sarah F Slaney, M D Poole, Louise J Pulleyn, Paul Rutland, Anthony D Hockley, M J Wake, J H Goldin, R M WinterAbstract:Craniosynostosis, which affects approximately 1 in 2000 children, is the result of the abnormal development and/or premature fusion of the cranial sutures. Studies of mutations in patients with craniosynostosis have shown that the family of fibroblast growth factor receptor genes are extremely important in the correct formation of the skull, and digits. Mutations in the third immunoglobulin domain of fibroblast growth factor receptor 2 (FGFR2), in part of the molecule corresponding to a tissue specific isoform (IIIc), can cause both Crouzon and Pfeiffer Syndromes. Two specific mutations in the linking region between the second and third immunoglobulin domains of FGFR2 occur in Apert Syndrome. We present here mutations associated with the Crouzon Syndrome, also in the third immunoglobulin domain but in an upstream exon. This exon is expressed in both tissue isoforms. Five different mutations were detected in 11 unrelated individuals. A cysteine to phenylalanine change was found in six individuals. This cysteine forms half of the disulphide bridge maintaining the secondary structure of the immunoglobulin domain. The first deletion within an FGFR gene is reported. Together with mutations in exon IIIc these account for 25 mutations out of 40 Crouzon patients studied in our combined series (5).
-
Apert Syndrome results from localized mutations of FGFR2 and is allelic with Crouzon Syndrome
Nature Genetics, 1995Co-Authors: Andrew O M Wilkie, David J. David, Richard D. Hayward, Michael Oldridge, Sarah F Slaney, Louise J Pulleyn, Anthony D Hockley, Michael D. Poole, Geraldine J. Ashworth, Paul RutlandAbstract:Apert Syndrome is a distinctive human malformation comprising craniosynostosis and severe syndactyly of the hands and feet. We have identified specific missense substitutions involving adjacent amino acids (Ser252Trp and Pro253Arg) in the linker between the second and third extracellular immunoglobulin (Ig) domains of fibroblast growth factor receptor 2 (FGFR2) in all 40 unrelated cases of Apert Syndrome studied. Crouzon Syndrome, characterized by craniosynostosis but normal limbs, was previously shown to result from allelic mutations of the third Ig domain of FGFR2. The contrasting effects of these mutations provide a genetic resource for dissecting the complex effects of signal transduction through FGFRs in cranial and limb morphogenesis.