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

We previously discovered a novel missense mutation (Lys650Met) in the tyros ine kinase domain of the fibroblast growth factor receptor 3 (FGFR3) gene i n four unrelated individuals with a condition we called "severe achondropla sia with developmental delay and acanthosis nigricans" (SADDAN) [Tavormina et al,, 1999: Am. J. Hum. Grenet. 64:722-731], Here we present a more detai led clinical account of the SADDAN phenotype, The FGFR3 Lys650Met mutation results in severe disturbances in endochondral bone growth that approach an d overlap those observed in thanatophoric dysplasia, type I. However, this mutation is most often compatible with survival into adulthood, Other unusu al bone deformities, such as femoral bowing with reverse (i.e., posterior a pex) 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, sei zures and severe developmental delays are observed in surviving SADDAN pati ents. Despite its location within the same FGFR3 codon as the thanatophoric dysplasia type II mutation (Lys650Glu) and a similar effect on constitutiv e activation of the FGFR3 tyrosine kinase, the Lys650Met is not associated with cloverleaf skull or craniosynostosis. Am. J, Med, Genet. 85:53-65, 199 9. (C) 1999 Wiley-Liss, Inc.