ClinVar Genomic variation as it relates to human health

Depressed nasal ridge (present) , Facial asymmetry (present) , Epicanthus (present) , Brachydactyly (present) , Bicoronal synostosis (present) , Abnormality of the helix (present) , Anteverted nares (present) , Sparse and thin eyebrow (present) (less)

Bellus et al. (1996) described a pro250-to-arg (P250R) amino acid substitution in FGFR3 (caused by a C-to-G transversion at position 749 of the coding cDNA sequence) in 10 unrelated patients with nonsyndromic autosomal dominant or sporadic craniosynostosis. This mutation is in the extracellular domain of the FGFR3 protein and occurs precisely at the position within the FGFR3 protein analogous to that of mutations in FGFR1 (P252R; 136350.0001) and FGFR2 (P253R; 176943.0011), previously reported in Pfeiffer (101600) and Apert syndromes, respectively. They pictured the craniofacial and extremity anomalies in some of these cases. Muenke et al. (1997) provided extensive information on a series of 61 individuals from 20 unrelated families in which coronal craniosynostosis is due to this mutation, defining a new clinical syndrome that is referred to as Muenke nonsyndromic coronal craniosynostosis (602849). At about the same time, Moloney et al. (1997) studied 26 patients with coronal craniosynostosis but no syndromic diagnosis to determine the frequency of the 749C-G (pro250-to-arg) mutation in FGFR3. Heterozygosity for the mutation was found in 8 (31%) of the 26 probands. In 2 cases, the mutation showed autosomal dominant transmission with evidence of variable expressivity; the remaining 6 cases were sporadic. Moloney et al. (1997) pointed out that the 749C nucleotide has one of the highest mutation rates described in the human genome. Reardon et al. (1997) reported 9 individuals with the P250R mutation. The authors documented a variable clinical presentation and contrasted this with the phenotype produced by the analogous mutation in FGFR1 (P252R; 136350.0001) and FGFR2 (P253R; 176943.0011). In particular, Reardon et al. (1997) noted mental retardation in 4 of the 9 cases, which they reported was unrelated to the management of the craniosynostosis. Reardon et al. (1997) suggested that there was a significant overlap between Saethre-Chotzen syndrome (101400), a common autosomal dominant condition of craniosynostosis and limb anomalies, and the phenotype produced by this mutation. They also noted unisutural craniosynostosis in 3 of the 9 cases to emphasize the caution with which the recurrence risks should be approached in craniosynostosis. In a study of 32 unrelated patients with features of Saethre-Chotzen syndrome, Paznekas et al. (1998) identified 7 families with the P250R mutation of the FGFR3 gene. The overlap in clinical features and the presence, in the same genes, of mutations for more than one craniosynostotic condition, such as Saethre-Chotzen, Crouzon, and Pfeiffer syndromes, suggested that the TWIST1 gene (601622), which is most frequently the site of mutations causing Saethre-Chotzen syndrome, and FGFRs are components of the same molecular pathway involved in the modulation of craniofacial and limb development in humans. The clinical features of the patients who were referred with the possible diagnosis of Saethre-Chotzen syndrome and who were found to have the FGFR3 mutation were not obviously different from those of individuals with the TWIST1 mutation. Golla et al. (1997) described a large German family with the P250R mutation in which there was also considerable phenotypic variability among individuals with the identical mutation. The clinical features in this family had been described by von Gernet et al. (1996). Gripp et al. (1998) found the P250R mutation in 4 of 37 patients with synostotic anterior plagiocephaly (literally 'oblique head'). In 3 mutation-positive patients with full parental studies, a parent with an extremely mild phenotype was found to carry the same mutation. None of the 6 patients with nonsynostotic plagiocephaly and none of the 4 patients with additional suture synostosis had the FGFR3 mutation. Hollway et al. (1998) found the P250R mutation in FGFR3 in an extensive family with craniosynostosis and deafness, extending through 5 generations. The deafness was congenital, bilateral, sensorineural, and of moderate degree. Four family members had craniosynostosis evident at clinical review; 2 required surgery, and 1 was symptomatically deaf. Thirteen other affected members of the family had no evidence of craniosynostosis but were either symptomatically deaf or required bilateral hearing aids. Hollway et al. (1998) thought that the craniosynostosis and deafness were not coincidentally associated and that the low penetrance of symptomatic craniosynostosis in this family raised the possibility that some families with the P250R mutation may present with deafness only. They pointed out that 1 locus for autosomal dominant nonsyndromal deafness (DFNA6; 600965) maps to 4p16.3, the location of the FGFR3 gene. Robin et al. (1998) described a woman who was completely clinically and radiologically normal but was carrying the P250R mutation. Graham et al. (1998) suggested that carpal-tarsal fusion may be the most specific finding for the FGFR3 mutation, being present in some individuals who did not have craniosynostosis. The patient reported by Robin et al. (1998) did not have carpal-tarsal fusion. Lajeunie et al. (1999) studied 62 patients with sporadic or familial forms of coronal craniosynostosis. The P250R mutation was identified in 20 probands from 27 unrelated families (74%), while only 6 of 35 sporadic cases (17%) were found to have this mutation. In both familial and sporadic cases, females were more severely affected, with 68% of females but only 35% of males having brachycephaly. In the most severely affected individuals, bicoronal craniosynostosis was associated with hypertelorism and marked bulging of the temporal fossae, features that Lajeunie et al. (1999) concluded might be helpful for clinical diagnosis. Lajeunie et al. (1999) concluded that the P250R mutation is most often familial and is associated with a more severe phenotype in females than in males. El Ghouzzi et al. (1999) found the P250R mutation in 2 of 22 cases of Saethre-Chotzen syndrome. The largest number of cases (16/22) were found to have mutations in the TWIST1 gene. In 4 of the 22 cases, no mutations were found in either TWIST1 or FGFR3. Roscioli et al. (2001) described a patient with severe premature calvarial synostosis and epidermal hyperplasia. Although the phenotype was consistent with that of a mild presentation of Beare-Stevenson syndrome (123790), molecular analysis of FGFR2 (176943) revealed wildtype sequence only. Molecular analysis of FGFR3 identified a heterozygous P250R missense mutation in both the proposita and her mildly affected father. The cutis gyrata in the daughter was located on the left palm, accompanied by deep skin creasing of both soles. In addition, a clearly demarcated darkened linear streak (initially macular) was present on the left forearm. At the age of 18 months, normal skin overlaid the neck and flexural regions. The father showed macrocephaly with some excessive creasing/thickening of the forehead skin and hypertelorism, but the skull was otherwise normal with no evidence of past premature craniosynostosis. This case extended the clinical spectrum of the P250R mutation to encompass epidermal hyperplasia and documented the phenomenon of activated FGFR receptors stimulating common downstream developmental pathways, resulting in overlapping clinical outcomes. Lowry et al. (2001) reported a family in which members with coronal craniosynostosis, skeletal abnormalities of the hands, and sensorineural hearing loss had the P250R mutation. One family member also had a Sprengel shoulder anomaly (184400) and multiple cervical spine anomalies consistent with Klippel-Feil anomaly (118100). The authors reported an additional case with an identical phenotype without the mutation. Rannan-Eliya et al. (2004) studied 19 cases of Muenke syndrome due to de novo P250R mutations in FGFR3. All 10 informative cases were of paternal origin; the average paternal age at birth for all 19 cases was 34.7 years. The authors noted that exclusive paternal origin and increased paternal age had previously been described for the G380R mutation in FGFR3 (134934.0001) and mutations in FGFR2 (e.g., S252W, 176943.0010). By surface plasmon resonance analysis and x-ray crystallography, Ibrahimi et al. (2004) characterized the effects of proline-to-arginine mutations in FGFR1c and FGFR3c on ligand binding. Both the FGFR1c P252R and FGFR3c P250R mutations exhibited an enhancement in ligand binding in comparison to their respective wildtype receptors. Binding of both mutant receptors to FGF9 (600921) was notably enhanced and implicated FGF9 as a potential pathophysiologic ligand for mutant FGFRs in mediating craniosynostosis. The crystal structure of P252R mutant in complex with FGF2 (134920) demonstrated that enhanced ligand binding was due to an additional set of receptor-ligand hydrogen bonds, similar to those gain-of-function interactions that occur in the crystal structure of FGFR2c P253R (176943.0011) mutant in complex with FGF2. However, unlike the P253R mutant, neither the FGFR1c P250R mutant nor the FGFR3c P250R mutant bound appreciably to FGF7 (148180) or FGF10 (602115). Ibrahimi et al. (2004) suggested that this might explain why limb phenotypes observed in type I Pfeiffer syndrome and Muenke syndrome are less severe than limb abnormalities observed in Apert syndrome. Almeida et al. (2009) reported a Portuguese patient with Muenke syndrome resulting from the P250R mutation who developed an osteochondroma in the proximal metaphysis of the left tibia. In a cohort of 182 Spanish probands with craniosynostosis, Paumard-Hernandez et al. (2015) found the most frequent mutation to be P250R in FGFR3, which was detected in 24 patients (13.2% of the cohort). The authors noted that this was somewhat lower than the 24% detected in a UK study of craniosynostosis patients by Wilkie et al. (2010). (less)

Bellus et al. (1996) described a pro250-to-arg (P250R) amino acid substitution in FGFR3 (caused by a C-to-G transversion at position 749 of the coding cDNA sequence) in 10 unrelated patients with nonsyndromic autosomal dominant or sporadic craniosynostosis. This mutation is in the extracellular domain of the FGFR3 protein and occurs precisely at the position within the FGFR3 protein analogous to that of mutations in FGFR1 (P252R; 136350.0001) and FGFR2 (P253R; 176943.0011), previously reported in Pfeiffer (101600) and Apert syndromes, respectively. They pictured the craniofacial and extremity anomalies in some of these cases. Muenke et al. (1997) provided extensive information on a series of 61 individuals from 20 unrelated families in which coronal craniosynostosis is due to this mutation, defining a new clinical syndrome that is referred to as Muenke nonsyndromic coronal craniosynostosis (602849). At about the same time, Moloney et al. (1997) studied 26 patients with coronal craniosynostosis but no syndromic diagnosis to determine the frequency of the 749C-G (pro250-to-arg) mutation in FGFR3. Heterozygosity for the mutation was found in 8 (31%) of the 26 probands. In 2 cases, the mutation showed autosomal dominant transmission with evidence of variable expressivity; the remaining 6 cases were sporadic. Moloney et al. (1997) pointed out that the 749C nucleotide has one of the highest mutation rates described in the human genome. Reardon et al. (1997) reported 9 individuals with the P250R mutation. The authors documented a variable clinical presentation and contrasted this with the phenotype produced by the analogous mutation in FGFR1 (P252R; 136350.0001) and FGFR2 (P253R; 176943.0011). In particular, Reardon et al. (1997) noted mental retardation in 4 of the 9 cases, which they reported was unrelated to the management of the craniosynostosis. Reardon et al. (1997) suggested that there was a significant overlap between Saethre-Chotzen syndrome (101400), a common autosomal dominant condition of craniosynostosis and limb anomalies, and the phenotype produced by this mutation. They also noted unisutural craniosynostosis in 3 of the 9 cases to emphasize the caution with which the recurrence risks should be approached in craniosynostosis. In a study of 32 unrelated patients with features of Saethre-Chotzen syndrome, Paznekas et al. (1998) identified 7 families with the P250R mutation of the FGFR3 gene. The overlap in clinical features and the presence, in the same genes, of mutations for more than one craniosynostotic condition, such as Saethre-Chotzen, Crouzon, and Pfeiffer syndromes, suggested that the TWIST1 gene (601622), which is most frequently the site of mutations causing Saethre-Chotzen syndrome, and FGFRs are components of the same molecular pathway involved in the modulation of craniofacial and limb development in humans. The clinical features of the patients who were referred with the possible diagnosis of Saethre-Chotzen syndrome and who were found to have the FGFR3 mutation were not obviously different from those of individuals with the TWIST1 mutation. Golla et al. (1997) described a large German family with the P250R mutation in which there was also considerable phenotypic variability among individuals with the identical mutation. The clinical features in this family had been described by von Gernet et al. (1996). Gripp et al. (1998) found the P250R mutation in 4 of 37 patients with synostotic anterior plagiocephaly (literally 'oblique head'). In 3 mutation-positive patients with full parental studies, a parent with an extremely mild phenotype was found to carry the same mutation. None of the 6 patients with nonsynostotic plagiocephaly and none of the 4 patients with additional suture synostosis had the FGFR3 mutation. Hollway et al. (1998) found the P250R mutation in FGFR3 in an extensive family with craniosynostosis and deafness, extending through 5 generations. The deafness was congenital, bilateral, sensorineural, and of moderate degree. Four family members had craniosynostosis evident at clinical review; 2 required surgery, and 1 was symptomatically deaf. Thirteen other affected members of the family had no evidence of craniosynostosis but were either symptomatically deaf or required bilateral hearing aids. Hollway et al. (1998) thought that the craniosynostosis and deafness were not coincidentally associated and that the low penetrance of symptomatic craniosynostosis in this family raised the possibility that some families with the P250R mutation may present with deafness only. They pointed out that 1 locus for autosomal dominant nonsyndromal deafness (DFNA6; 600965) maps to 4p16.3, the location of the FGFR3 gene. Robin et al. (1998) described a woman who was completely clinically and radiologically normal but was carrying the P250R mutation. Graham et al. (1998) suggested that carpal-tarsal fusion may be the most specific finding for the FGFR3 mutation, being present in some individuals who did not have craniosynostosis. The patient reported by Robin et al. (1998) did not have carpal-tarsal fusion. Lajeunie et al. (1999) studied 62 patients with sporadic or familial forms of coronal craniosynostosis. The P250R mutation was identified in 20 probands from 27 unrelated families (74%), while only 6 of 35 sporadic cases (17%) were found to have this mutation. In both familial and sporadic cases, females were more severely affected, with 68% of females but only 35% of males having brachycephaly. In the most severely affected individuals, bicoronal craniosynostosis was associated with hypertelorism and marked bulging of the temporal fossae, features that Lajeunie et al. (1999) concluded might be helpful for clinical diagnosis. Lajeunie et al. (1999) concluded that the P250R mutation is most often familial and is associated with a more severe phenotype in females than in males. El Ghouzzi et al. (1999) found the P250R mutation in 2 of 22 cases of Saethre-Chotzen syndrome. The largest number of cases (16/22) were found to have mutations in the TWIST1 gene. In 4 of the 22 cases, no mutations were found in either TWIST1 or FGFR3. Roscioli et al. (2001) described a patient with severe premature calvarial synostosis and epidermal hyperplasia. Although the phenotype was consistent with that of a mild presentation of Beare-Stevenson syndrome (123790), molecular analysis of FGFR2 (176943) revealed wildtype sequence only. Molecular analysis of FGFR3 identified a heterozygous P250R missense mutation in both the proposita and her mildly affected father. The cutis gyrata in the daughter was located on the left palm, accompanied by deep skin creasing of both soles. In addition, a clearly demarcated darkened linear streak (initially macular) was present on the left forearm. At the age of 18 months, normal skin overlaid the neck and flexural regions. The father showed macrocephaly with some excessive creasing/thickening of the forehead skin and hypertelorism, but the skull was otherwise normal with no evidence of past premature craniosynostosis. This case extended the clinical spectrum of the P250R mutation to encompass epidermal hyperplasia and documented the phenomenon of activated FGFR receptors stimulating common downstream developmental pathways, resulting in overlapping clinical outcomes. Lowry et al. (2001) reported a family in which members with coronal craniosynostosis, skeletal abnormalities of the hands, and sensorineural hearing loss had the P250R mutation. One family member also had a Sprengel shoulder anomaly (184400) and multiple cervical spine anomalies consistent with Klippel-Feil anomaly (118100). The authors reported an additional case with an identical phenotype without the mutation. Rannan-Eliya et al. (2004) studied 19 cases of Muenke syndrome due to de novo P250R mutations in FGFR3. All 10 informative cases were of paternal origin; the average paternal age at birth for all 19 cases was 34.7 years. The authors noted that exclusive paternal origin and increased paternal age had previously been described for the G380R mutation in FGFR3 (134934.0001) and mutations in FGFR2 (e.g., S252W, 176943.0010). By surface plasmon resonance analysis and x-ray crystallography, Ibrahimi et al. (2004) characterized the effects of proline-to-arginine mutations in FGFR1c and FGFR3c on ligand binding. Both the FGFR1c P252R and FGFR3c P250R mutations exhibited an enhancement in ligand binding in comparison to their respective wildtype receptors. Binding of both mutant receptors to FGF9 (600921) was notably enhanced and implicated FGF9 as a potential pathophysiologic ligand for mutant FGFRs in mediating craniosynostosis. The crystal structure of P252R mutant in complex with FGF2 (134920) demonstrated that enhanced ligand binding was due to an additional set of receptor-ligand hydrogen bonds, similar to those gain-of-function interactions that occur in the crystal structure of FGFR2c P253R (176943.0011) mutant in complex with FGF2. However, unlike the P253R mutant, neither the FGFR1c P250R mutant nor the FGFR3c P250R mutant bound appreciably to FGF7 (148180) or FGF10 (602115). Ibrahimi et al. (2004) suggested that this might explain why limb phenotypes observed in type I Pfeiffer syndrome and Muenke syndrome are less severe than limb abnormalities observed in Apert syndrome. Almeida et al. (2009) reported a Portuguese patient with Muenke syndrome resulting from the P250R mutation who developed an osteochondroma in the proximal metaphysis of the left tibia. In a cohort of 182 Spanish probands with craniosynostosis, Paumard-Hernandez et al. (2015) found the most frequent mutation to be P250R in FGFR3, which was detected in 24 patients (13.2% of the cohort). The authors noted that this was somewhat lower than the 24% detected in a UK study of craniosynostosis patients by Wilkie et al. (2010). (less)