A unique point mutation in the FGFR3 gene defines a new craniosynostosis syndrome

Department of Pediatrics, University of Pennsylvania, Philadelphia, USA.
The American Journal of Human Genetics (Impact Factor: 10.93). 04/1997; 60(3):555-64.
Source: PubMed

ABSTRACT The underlying basis of many forms of syndromic craniosynostosis has been defined on a molecular level. However, many patients with familial or sporadic craniosynostosis do not have the classical findings of those craniosynostosis syndromes. Here we present 61 individuals from 20 unrelated families where coronal synostosis is due to an amino acid substitution (Pro250Arg) that results from a single point mutation in the fibroblast growth factor receptor 3 gene on chromosome 4p. In this instance, a new clinical syndrome is being defined on the basis of the molecular finding. In addition to the skull findings, some patients had abnormalities on radiographs of hands and feet, including thimble-like middle phalanges, coned epiphyses, and carpal and tarsal fusions. Brachydactyly was seen in some cases; none had clinically significant syndactyly or deviation of the great toe. Sensorineural hearing loss was present in some, and developmental delay was seen in a minority. While the radiological findings of hands and feet can be very helpful in diagnosing this syndrome, it is not in all cases clearly distinguishable on a clinical basis from other craniosynostosis syndromes. Therefore, this mutation should be tested for in patients with coronal synostosis.

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Available from: Donna M McDonald Mcginn, Sep 29, 2015
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    • "The first gene that was found to be in association with craniosynostosis was the msh homeobox 2 (MSX2) gene, a mutation that causes the Boston-type craniosynostosis (Jabs et al., 1993). In subsequent years more mutations were discovered in relation to syndromic craniosynostosis cases in the fibroblast growth factor receptor (FGFR) genes (Bellus et al., 1996; Jabs et al., 1994; Muenke et al., 1994, 1997; Reardon et al., 1994). At this point, more than 180 craniosynostoses and more than 60 different mutations in syndromic cases have been identified, the majority of which happen in the FGFR2 gene. "
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    ABSTRACT: The primary objective of this study was to perform new, relevant information about cranial suture closure in adults. Single nucleotide polymorphisms (SNPs) in targeted genes were examined, which encode factors that play an important role in cranial suture development and maintenance. Our hypothesis was that some of these genes and polymorphisms can influence the cranial suture obliteration status in adulthood as well. Ossification of cranial sutures was ascertained according to Meindl and Lovejoy's vault system (1985: Am J Phys Anthropol 68(1):57-66), and peripheral blood samples were collected during autopsy procedure of 106 individuals at the Department of Forensic and Insurance Medicine, Semmelweis University, Hungary. Genotyping of SNPs was conducted using competitive allele-specific polymerase chain reaction KASPar chemistry. Multivariate linear models were used to test whether SNP polymorphism of the investigated genes has a significant effect on the ectocranial suture synostosis in adults. The msh homeobox 1 (MSX1): rs3821947 polymorphism showed significant association with the extent of suture obliteration. Cranial suture closure in adults is a complex, multifactorial process. According to previous results MSX1 has a role in calvarial bone development and it has an effect on sutural mesenchyme in latter postnatal stages. Our results demonstrate MSX1 effects on suture obliteration in adulthood. These findings represent new, relevant information indicating that genetic background can have an impact on cranial suture closure in adults. Am. J. Hum. Biol., 2013. © 2013 Wiley Periodicals, Inc.
    American Journal of Human Biology 11/2013; 25(6). DOI:10.1002/ajhb.22459 · 1.70 Impact Factor
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    • "Documentation of the wide spectrum of skeletal anomalies present in the FGFR3‐related Muenke coronal craniosynostosis syndrome (CCS) further underscores a significant role for FGFRs in both endochondral and membranous bony development [Bellus et al., 1996; Moloney et al., 1997; Muenke et al., 1997; Graham et al., 1998] "
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    ABSTRACT: Craniosynostosis is one of the most common craniofacial disorders encountered in clinical genetics practice, with an overall incidence of 1 in 2,500. Between 30% and 70% of syndromic craniosynostoses are caused by mutations in hotspots in the fibroblast growth factor receptor (FGFR) genes or in the TWIST1 gene with the difference in detection rates likely to be related to different study populations within craniofacial centers. Here we present results from molecular testing of an Australia and New Zealand cohort of 630 individuals with a diagnosis of craniosynostosis. Data were obtained by Sanger sequencing of FGFR1, FGFR2, and FGFR3 hotspot exons and the TWIST1 gene, as well as copy number detection of TWIST1. Of the 630 probands, there were 231 who had one of 80 distinct mutations (36%). Among the 80 mutations, 17 novel sequence variants were detected in three of the four genes screened. In addition to the proband cohort there were 96 individuals who underwent predictive or prenatal testing as part of family studies. Dysmorphic features consistent with the known FGFR1-3/TWIST1-associated syndromes were predictive for mutation detection. We also show a statistically significant association between splice site mutations in FGFR2 and a clinical diagnosis of Pfeiffer syndrome, more severe clinical phenotypes associated with FGFR2 exon 10 versus exon 8 mutations, and more frequent surgical procedures in the presence of a pathogenic mutation. Targeting gene hot spot areas for mutation analysis is a useful strategy to maximize the success of molecular diagnosis for individuals with craniosynostosis. © 2013 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part C Seminars in Medical Genetics 10/2013; 163(4). DOI:10.1002/ajmg.c.31378 · 3.91 Impact Factor
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    • "Compared to the major effects of the GOF mutations of FGFR1 and FGFR2 on the skulls that are formed through intramembranous ossification, GOF mutations in FGFR3 have been found to mainly affect skeleton formed through endochondral ossification, leading to several types of chondrodysplasia including achondroplasia (ACH), hypochondroplasia (HCH), and thanatophoric dysplasia (TD). GOF mutations in FGFR3 have also been found to cause premature suture fusion, leading to craniosynostoses.A391E mutation in FGFR3 is responsible for Crouzonodermoskeletal syndrome (CDS), a disease with Crouzon-like phenotype and associated dermal thickening and hyperpigmentation.FGFR3 P250R mutation has been found in humans responsible for Muenke Syndrome (Meyers et al., 1995; Wilkes et al., 1996; Muenke et al., 1997; Arnaud-Lopez et al., 2007; Su et al., 2008a). Furthermore, patients with TD frequently exhibit severe craniosynostoses (Tavormina et al., 1995). "
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    ABSTRACT: Fibroblast growth factor (FGF)/FGF (FGFR) signaling is an important pathway involved in skeletal development. Missense mutations in FGFs and FGFRs were found clinically to cause multiple congenital skeleton diseases including chondrodysplasia, craniosynostosis, syndromes with dysregulated phosphate metabolism. FGFs/FGFRs also have crucial roles in bone fracture repair and bone regeneration. Understanding the molecular mechanisms for the role of FGFs/FGFRs in the regulation of skeletal development, genetic skeletal diseases, and fracture healing will ultimately lead to better treatment of skeleton diseases caused by mutations of FGFs/FGFRs and fracture. This review summarizes the major findings on the role of FGF signaling in skeletal development, genetic skeletal diseases and bone healing, and discusses issues that remain to be resolved in applying FGF signaling-related measures to promote bone healing. This review has also provided a perspective view on future work for exploring the roles and action mechanisms of FGF signaling in skeletal development, genetic skeletal diseases, and fracture healing.
    Journal of Cellular Physiology 12/2012; 227(12):3731-43. DOI:10.1002/jcp.24083 · 3.84 Impact Factor
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