title: Somatic and germline mosaicism for a R248C missense mutation in FGFR3, resulting in a skeletal dysplasia distinct from thanatophoric dysplasia.
abstract: In this communication, we report the identification of a mosaic R248C missense mutation in the IgII-III linker region of the gene encoding the fibroblast growth factor receptor-3 (FGFR3), in an individual who manifests a skeletal dysplasia and epidermal hyperplasia. By means of Denaturing High Performance Liquid Chromatography (DHPLC), we determined that 25% of her lymphocytes are heterozygous for this particular missense mutation in FGFR3, and that 12.5% of her lymphocyte-derived genomic DNA encodes a cysteine residue at this position. The proposita has disproportionate short stature, radial head dislocation, coxa vara, and bowing of some of the long bones, associated with an S-shaped deformity of the humerus, accompanied by widespread acanthosis nigricans in the integument. These features do not match any previously described skeletal dysplasia. Further, the proposita's only pregnancy ended in the delivery of a fetus manifesting a lethal short-limbed dwarfism with pulmonary hypoplasia, strongly suggestive of an undiagnosed thanatophoric dysplasia. These findings confirm the proposita to be a somatic and germline mosaic for this particular missense mutation in FGFR3. Thus far, all reported FGFR3 R248C mutations have resulted in thanatophoric dysplasia type I (TDI).
authors.affiliation: Department of Surgery, University of Queensland, Royal Brisbane Hospital, Herston Hospitals Campus, Brisbane, Australia.
authors.forename: Valentine J
authors.initials: VJ
authors.lastname: Hyland
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Robertson
authors.forename: Simon
authors.initials: S
authors.lastname: Flanagan
authors.forename: Ravi
authors.initials: R
authors.lastname: Savarirayan
authors.forename: Tony
authors.initials: T
authors.lastname: Roscioli
authors.forename: John
authors.initials: J
authors.lastname: Masel
authors.forename: Mark
authors.initials: M
authors.lastname: Hayes
authors.forename: Ian A
authors.initials: IA
authors.lastname: Glass
mesh_terms: D000052:Acanthosis Nigricans / Q000235:genetics / Q000473:pathology; D001827:Body Height; D001848:Bone Diseases, Developmental / Q000000981:diagnostic imaging / Q000235:genetics*; D002851:Chromatography, High Pressure Liquid; D003545:Cysteine / Q000235:genetics; D005260:Female; D006579:Heterozygote; D006801:Humans; D006965:Hyperplasia / Q000235:genetics; D008875:Middle Aged; D009030:Mosaicism / Q000235:genetics*; D009139:Musculoskeletal Abnormalities / Q000235:genetics*; D020125:Mutation, Missense; D011505:Protein-Tyrosine Kinases; D011859:Radiography; D051498:Receptor, Fibroblast Growth Factor, Type 3; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics*; D017422:Sequence Analysis, DNA; D013796:Thanatophoric Dysplasia / Q000235:genetics*
chemical_list: D017468:Receptors, Fibroblast Growth Factor; C496365:FGFR3 protein, human; D011505:Protein-Tyrosine Kinases; D051498:Receptor, Fibroblast Growth Factor, Type 3; D003545:Cysteine