A unique point mutation in the fibroblast growth factor receptor 3 gene (FGFR3) defines a new craniosynostosis syndrome.

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.

[1]  R. Friesel,et al.  Ligand-independent Activation of Fibroblast Growth Factor Receptors by Point Mutations in the Extracellular, Transmembrane, and Kinase Domains* , 1996, The Journal of Biological Chemistry.

[2]  E. Zackai,et al.  Identical mutations in three different fibroblast growth factor receptor genes in autosomal dominant craniosynostosis syndromes , 1996, Nature Genetics.

[3]  W. Reardon,et al.  A recurrent mutation, ala391glu, in the transmembrane region of FGFR3 causes Crouzon syndrome and acanthosis nigricans. , 1996, Journal of medical genetics.

[4]  M. Bamshad,et al.  Fibroblast growth factor receptor 2 mutations in Beare–Stevenson cutis gyrata syndrome , 1996, Nature Genetics.

[5]  D. Ornitz,et al.  Graded activation of fibroblast growth factor receptor 3 by mutations causing achondroplasia and thanatophoric dysplasia , 1996, Nature Genetics.

[6]  T. Meitinger,et al.  Craniosynostosis suggestive of Saethre-Chotzen syndrome: clinical description of a large kindred and exclusion of candidate regions on 7p. , 1996, American journal of medical genetics.

[7]  Steven A. Wall,et al.  Exclusive paternal origin of new mutations in Apert syndrome , 1996, Nature Genetics.

[8]  Gary W. Harding,et al.  Skeletal overgrowth and deafness in mice lacking fibroblast growth factor receptor 3 , 1996, Nature Genetics.

[9]  A. Munnich,et al.  Missense FGFR3 mutations create cysteine residues in thanatophoric dwarfism type I (TD1). , 1996, Human molecular genetics.

[10]  P. Leder,et al.  Fibroblast Growth Factor Receptor 3 Is a Negative Regulator of Bone Growth , 1996, Cell.

[11]  E. Jabs,et al.  FGFR2 exon IIIa and IIIc mutations in Crouzon, Jackson-Weiss, and Pfeiffer syndromes: evidence for missense changes, insertions, and a deletion due to alternative RNA splicing. , 1996, American journal of human genetics.

[12]  I. Munro,et al.  Fibroblast growth factor receptor 3 (FGFR3) transmembrane mutation in Crouzon syndrome with acanthosis nigricans , 1995, Nature Genetics.

[13]  D. Rimoin,et al.  Another mutation that results in the substitution of an unpaired cysteine residue in the extracellular domain of FGFR3 in thanatophoric dysplasia type I. , 1995, Human molecular genetics.

[14]  H. Losken,et al.  Crouzon syndrome: mutations in two spliceoforms of FGFR2 and a common point mutation shared with Jackson-Weiss syndrome. , 1995, Human molecular genetics.

[15]  M. Muenke,et al.  Fibroblast-growth-factor receptor mutations in human skeletal disorders. , 1995, Trends in genetics : TIG.

[16]  E. Jabs,et al.  Analysis of phenotypic features and FGFR2 mutations in Apert syndrome. , 1995, American journal of human genetics.

[17]  E. Jabs,et al.  Novel FGFR2 mutations in Crouzon and Jackson-Weiss syndromes show allelic heterogeneity and phenotypic variability. , 1995, Human molecular genetics.

[18]  R. Winter,et al.  Mutations in the third immunoglobulin domain of the fibroblast growth factor receptor-2 gene in Crouzon syndrome. , 1995, Human molecular genetics.

[19]  J. Heath,et al.  Functions of fibroblast growth factors and their receptors , 1995, Current Biology.

[20]  M. Cohen,et al.  Craniosynostoses: phenotypic/molecular correlations. , 1995, American journal of medical genetics.

[21]  E. Haan,et al.  Localization of craniosynostosis Adelaide type to 4p16. , 1995, Human molecular genetics.

[22]  D. Rimoin,et al.  Thanatophoric dysplasia (types I and II) caused by distinct mutations in fibroblast growth factor receptor 3 , 1995, Nature Genetics.

[23]  E. Zackai,et al.  Mutations in FGFR1 and FGFR2 cause familial and sporadic Pfeiffer syndrome. , 1995, Human molecular genetics.

[24]  W. Reardon,et al.  Saethre-Chotzen syndrome associated with balanced translocations involving 7p21: three further families. , 1995, Journal of medical genetics.

[25]  C. Bonaïti‐pellié,et al.  Genetic study of nonsyndromic coronal craniosynostosis. , 1995, American journal of medical genetics.

[26]  A. Munnich,et al.  FGFR2 mutations in Pfeiffer syndrome , 1995, Nature Genetics.

[27]  W. Reardon,et al.  Identical mutations in the FGFR2 gene cause both Pfeiffer and Crouzon syndrome phenotypes , 1995, Nature Genetics.

[28]  W. Reardon,et al.  Apert syndrome results from localized mutations of FGFR2 and is allelic with Crouzon syndrome , 1995, Nature Genetics.

[29]  I. Kaitila,et al.  Achondroplasia is defined by recurrent G380R mutations of FGFR3. , 1995, American journal of human genetics.

[30]  E. Zackai,et al.  Linkage of Pfeiffer syndrome to chromosome 8 centromere and evidence for genetic heterogeneity. , 1994, Human molecular genetics.

[31]  W. Reardon,et al.  A common mutation in the fibroblast growth factor receptor 1 gene in Pfeiffer syndrome , 1994, Nature Genetics.

[32]  M. Eccles,et al.  Jackson-Weiss and Crouzon syndromes are allelic with mutations in fibroblast growth factor receptor 2 , 1994, Nature Genetics.

[33]  Arnold Munnich,et al.  Mutations in the gene encoding fibroblast growth factor receptor-3 in achondroplasia , 1994, Nature.

[34]  Sue Malcolm,et al.  Mutations in the fibroblast growth factor receptor 2 gene cause Crouzon syndrome , 1994, Nature Genetics.

[35]  D. Church,et al.  Mutations in the transmembrane domain of FGFR3 cause the most common genetic form of dwarfism, achondroplasia , 1994, Cell.

[36]  I. Glass,et al.  A distinct autosomal dominant craniosynostosis-brachydactyly syndrome. , 1994, Clinical dysmorphology.

[37]  E. Haan,et al.  Jackson-Weiss syndrome: clinical and radiological findings in a large kindred and exclusion of the gene from 7p21 and 5qter. , 1994, American journal of medical genetics.

[38]  J. Weissenbach,et al.  Evidence for locus heterogeneity in acrocephalosyndactyly: a refined localization for the Saethre-Chotzen syndrome locus on distal chromosome 7p--and exclusion of Jackson-Weiss syndrome from craniosynostosis loci on 7p and 5q. , 1994, American journal of human genetics.

[39]  E. Zackai,et al.  Saethre-Chotzen syndrome with familial translocation at chromosome 7p22. , 1993, American journal of medical genetics.

[40]  W. Reardon,et al.  Cytogenetic evidence that the Saethre-Chotzen gene maps to 7p21.2. , 1993, American journal of medical genetics.

[41]  R. Winter,et al.  The mapping of a gene for craniosynostosis: evidence for linkage of the Saethre-Chotzen syndrome to distal chromosome 7p. , 1992, Journal of medical genetics.

[42]  A. Hunter,et al.  Craniosynostosis. II. Coronal synostosis: its familial characteristics and associated clinical findings in 109 patients lacking bilateral polysyndactyly or syndactyly. , 1977, Teratology.

[43]  L. Weiss,et al.  Craniosynostosis, midfacial hypoplasia and foot abnormalities: an autosomal dominant phenotype in a large Amish kindred. , 1976, The Journal of pediatrics.

[44]  J. Cracco,et al.  Pfeiffer syndrome. An unusual type of acrocephalosyndactyly with broad thumbs and great toes. , 1971, American journal of diseases of children.

[45]  J. Cracco,et al.  Pfeiffer syndrome: an unusual type of acrocephalosyndactyl with broad thumbs and great toes. , 1970, Neurology.

[46]  E. Green,et al.  Mutations in TWIST, a basic helix–loop–helix transcription factor, in Saethre-Chotzen syndrome , 1997, Nature Genetics.

[47]  P. Bénit,et al.  Mutations of the TWIST gene in the Saethre-Chotzene syndrome , 1997, Nature Genetics.

[48]  I. Kaitila,et al.  A recurrent mutation in the tyrosine kinase domain of fibroblast growth factor receptor 3 causes hypochondroplasia , 1995, Nature Genetics.

[49]  S. Clarren,et al.  Genetic heterogeneity among craniosynostosis syndromes: mapping the Saethre-Chotzen syndrome locus between D7S513 and D7S516 and exclusion of Jackson-Weiss and Crouzon syndrome loci from 7p. , 1994, Genomics.

[50]  Y. Seino,et al.  Craniosynostosis and hemizygosity for D7S135 caused by a de novo and apparently balanced t(6;7) translocation. , 1994, American journal of medical genetics.