title: Severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN): phenotypic analysis of a new skeletal dysplasia caused by a Lys650Met mutation in fibroblast growth factor receptor 3.
abstract: We previously discovered a novel missense mutation (Lys650Met) in the tyrosine kinase domain of the fibroblast growth factor receptor 3 (FGFR3) gene in four unrelated individuals with a condition we called "severe achondroplasia with developmental delay and acanthosis nigricans" (SADDAN) [Tavormina et al., 1999: Am. J. Hum. Genet. 64:722-731]. Here we present a more detailed clinical account of the SADDAN phenotype. The FGFR3 Lys650Met mutation results in severe disturbances in endochondral bone growth that approach and overlap those observed in thanatophoric dysplasia, type I. However, this mutation is most often compatible with survival into adulthood. Other unusual bone deformities, such as femoral bowing with reverse (i.e., posterior apex) tibial and fibular bowing and "ram's horn" bowing of the clavicle, are also seen in some patients. In addition to skeletal dysplasia, progressive acanthosis nigricans, and central nervous system structural anomalies, seizures and severe developmental delays are observed in surviving SADDAN patients. Despite its location within the same FGFR3 codon as the thanatophoric dysplasia type II mutation (Lys650Glu) and a similar effect on constitutive activation of the FGFR3 tyrosine kinase, the Lys650Met is not associated with cloverleaf skull or craniosynostosis.
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA. gary.bellus@uchsc.edu
authors.forename: G A
authors.initials: GA
authors.lastname: Bellus
authors.forename: M J
authors.initials: MJ
authors.lastname: Bamshad
authors.forename: K A
authors.initials: KA
authors.lastname: Przylepa
authors.forename: J
authors.initials: J
authors.lastname: Dorst
authors.forename: R R
authors.initials: RR
authors.lastname: Lee
authors.forename: O
authors.initials: O
authors.lastname: Hurko
authors.forename: E W
authors.initials: EW
authors.lastname: Jabs
authors.forename: C J
authors.initials: CJ
authors.lastname: Curry
authors.forename: W R
authors.initials: WR
authors.lastname: Wilcox
authors.forename: R S
authors.initials: RS
authors.lastname: Lachman
authors.forename: D L
authors.initials: DL
authors.lastname: Rimoin
authors.forename: C A
authors.initials: CA
authors.lastname: Francomano
mesh_terms: D000052:Acanthosis Nigricans / Q000235:genetics*; D002658:Developmental Disabilities / Q000235:genetics*; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D008239:Lysine / Q000235:genetics; D008297:Male; D008715:Methionine / Q000235:genetics; D010009:Osteochondrodysplasias / Q000235:genetics*; D010641:Phenotype; D017354:Point Mutation; D011505:Protein-Tyrosine Kinases; D011859:Radiography; D051498:Receptor, Fibroblast Growth Factor, Type 3; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics*; D012886:Skull / Q000000981:diagnostic imaging / Q000473:pathology
chemical_list: D017468:Receptors, Fibroblast Growth Factor; D008715:Methionine; C496365:FGFR3 protein, human; D011505:Protein-Tyrosine Kinases; D051498:Receptor, Fibroblast Growth Factor, Type 3; D008239:Lysine