FGFR2 Mutations in Pfeiffer Syndrome

FGFR2 mutations in Pfeiffer syndrome

Sir-In the past few months, several genetic diseases have been ascribed to mutations in genes of the fibroblast growth factor receptor (FGFR) family, including achondroplasia (FGFR3) J-z, Crouzon syndrome (FGFR2)3 and 4 m/+ Pfeiffer syndrome (FGFR1) • In D321A addition, two clinically distinct N:Jl GIJ; AM craniosynostotic conditions, Jackson ~ Weiss and Crouzon syndromes, have c been ascribed to allelic mutations in the FGFR2 gene, suggesting that FGFR2mutations might have variable 5 phenotypic effects • We have recently FGFR2 found point mutations in the m/+ gene in two unrelated cases of Pfeiffer syndrome supporting the view that this craniosynostotic syndrome, is a 4 6 genetically heterogenous condition • • Pfeiffer syndrome is an autosomal dominant form of acrocephalo Fig. 1 Mutations of FGFR2 in two unrelated patients with craniofacial, hand syndactyly (ACS) characterized by and foot anomalies characteristic of Pfeiffer syndrome. Note midface craniosynostosis (brachycephaly retrusion, hypertelorism, proptosis and radiological evidence of enlargement type) with deviation and enlargement of thumb, with ankylosis of the second and third phalanges and the short, broad and deviated great toes. m, mutation; +, wild type sequence. The of the thumbs and great toes, sequence of wild type and mutant genes are shown and the arrow indicates brachymesophalangy, with pha the base substitution resulting in the mutation. langeal ankylosis and a varying degree of soft tissue syndactyly7.8. One of our sporadic cases and one familial form of ACS fulfilled the clinical criteria ofthe Pfeiffer syndrome, with particular respect to interphalangeal an aspartic acid into an alanine in the Elisabeth Lajeunie ankylosis (Fig. 1). There is no third immunoglobulin-like domain HongWeiMa confusion with Crouzon syndrome, of the protein (Fig. 1). These base Jacky Bonaventure in which no hand anomalies and substitutions were not found in 80 Arnold Munnich occasional radio-ulnar synostoses normal controls and the recurrent Martine Le Merrer have been reported, or Jackson-Weiss mutation in FGFRl previously Unite de Recherches sur les syndrome, which includes a tarsal reported in Pfeiffer syndrome4 was Handicaps Genetiques de l'Enfant, metatarsal coalescence and a medial not found in our patients (not INSERM U. 393, Hopital des deviation of broad great toes. shown). Enfants Malades, 149 rue de Sevres, Using a combination of single Muenke et aJ.4 emphasised the 75743 Paris Cedex 15, France strand conformation polymorphism genetic heterogeneity of Pfeiffer and sequence analyses of amplified syndrome, as not all familial forms of Dominique Renier exons in a case of sporadic Pfeiffer the disease were linked to the region Departement de Neurochirurgie, syndrome, we found an A to G of chromosome 8 where FGFRl Hopital des Enfants Malades, 6 transition in the 3' acceptor splice maps • The discovery of mutations 149 rue de Sevres, 75743 Paris site of the intron adjacent to exon B in the extracellular domain ofFGFR2 Cedex 15, France of FGFR2, disrupting the consensus in unrelated cases of Pfeiffer sequence required for the normal syndrome suggests that this condition 1. Shiang, R. et al. Ce/178, 335-342 (1994). processing ofthe RNA transcript (Fig. can be also accounted for by 2. Rousseau, F. et al. Nature 371, 252-254 (1994). 1). Whether this mutation results in mutations in FGFR2. Finally, our 3. Reardon, W. et al. Nature Genet. 8, 98-103 an aberrant protein or in functional observation gives strong support to (1994). 4. Muenke, M. et al. Nature Genet. 8, 269-274 haploinsufficiency for the exon B the variable clinical expression of (1994). containing splice variant is under FGFR2 mutations in man, which, 5. Jabs, E.W. et al. Nature Genet. 8, 275-279 (1994). investigation. with additional examples described 6. Robin, N.H. et al. Am. J. hum. Genet. 55, 9 In a familial form of Pfeiffer on page 165 of this issue , now A1171 (1994). 7. Pfeiffer, R.A. Z. Kinderheilk 90, 301-320 syndrome, we found an A to C account for four clinically distinct (1964). 9 transition at nucleotide 974 (codon craniosynostotic syndromes: Apert , 8. Cohen, M.M. Jr. Am. J. med. Genet. 45, 300- 5 307 (1993). 321) of the coding sequence (exon Crouzon3, Jackson-Weiss and 9. Wllkle,A.O.M.etal. Nature Genet. 9,165-172 B), creating an Eaei site and changing Pfeiffer syndromes. (1995).

108 Nature Genetics volume 9 february 1995