Genetically confirmed thanatophoric dysplasia with fibroblast growth factor receptor 3 mutation.

Thanatophoric dysplasia (TD), the most common lethal skeletal dysplasia, is a de novo genetic disease caused by a mutation in the fibroblast growth factor receptor 3 (FGFR3) gene. "Thanatophoric" means "dead bearing" in Greek. Because FGFR3 is the main modulator of bone maturation, typical features of TD include short extremities, curved femur, clover-leaf skull, small narrow chest, and platyspondyly. TD can be classified into two subgroups according to the morphologic findings, with prominent curved femur suggesting type I TD (TD 1) and with marked clover-leaf skull and relatively straight long bones, favoring type II TD (TD 2). However, considering the genetic profiles, TD 1 and TD 2 could be confidently delineated. Here, we report five genotype-phenotype correlated autopsy cases of TD. Five cases had stigmata of TD on antenatal ultrasonography. Terminations were done at gestational age 16 to 28weeks, after family consultation. In autopsy, all fetuses showed short limbs and clover-leaf skull. The microscopic examination of the bones showed disorganized growth plate, consistent with TD. However, some differences existed in gross and microscopic findings between cases. In genetic analyses, three cases revealed missense mutation of Y373C, while the remaining two cases had missense mutation of S371C and S249C each. They were hot spot mutations of TD 1. A correlation between genotype and phenotype was not apparent due to the limited number of the cases. Therefore, a molecular work up to identify the mutation of FGFR3 is indispensable for TD diagnosis in the era of precision medicine for genetic consultation and future targeted therapy.