Platyspondylic lethal skeletal dysplasia, San Diego type, is caused by FGFR3 mutations

The platyspondylic lethal skeletal dysplasias (PLSDs) are a heterogeneous g roup of short-limb dwarfing conditions. The most common form of PLSD is tha natophoric dysplasia (TD), which has been divided into two types (TD1 and T D2). Three other types of PLSD, or TD variants (San Diego, Torrance, and Lu ton), have been distinguished from TD, The most notable difference between TD and the variants is the presence of large rough endoplasmic reticulum (r ER) inclusion bodies within chondrocytes of the variants. We examined 22 ca ses of TD variants for the presence of missense mutations in the fibroblast growth factor receptor 3 (FGFR3) gene. All 17 cases of the San Diego type (PLSD-SD) were heterozygous for the same FGFR3 mutations found in TD1, No m utations were identified in the Torrance and Luton types. Large inclusion b odies were found in all 14 cases of PLSD-SD, Similar inclusion bodies were present in two of 72 TD1 cases, but not in 39 controls. The material retain ed within the rER stained only with antibody to the FGFR3 protein. The radi ographic and morphologic differences between TD and PLSD-SD may be a conseq uence of other genetic factors, perhaps in the processing of mutant FGFR3 m olecules within the rER, The presence of rER inclusion bodies cannot reliab ly discriminate between closely related skeletal dysplasias. Am. J. Med. Ge net, 84:476-480, 1999. (C) 1999 Wiley-Liss, Inc.