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


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
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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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    • "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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    • "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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