Molecular, radiologic, and histopathologic correlations in thanatophoric dysplasia.

Various mutations in the fibroblast growth factor receptor 3 (FGFR3) gene have recently been reported in thanatophoric dysplasia (TD). We examined the clinical, radiographic, and histologic findings in 91 cases from the International Skeletal Dysplasia Registry and correlated them with the specific FGFR3 mutation. Every case of TD examined had an identifiable FGFR3 mutation. Radiographically, all of the cases with the Lys650Glu substitution demonstrated straight femora with craniosynostosis, and frequently a cloverleaf skull (CS) was demonstrated. In all other cases, the femora were curved, and CS was infrequently present but was occasionally as severe as TD with the Lys650Glu substitution. Histopathologically, all of the cases shared similar abnormalities, but cases with the Lys650Glu substitution had better preservation of the growth plate. Cases with the Tyr373Cys substitution tended to have more severe radiographic manifestations than the Arg248Cys cases, but there was overlap in the phenotypic spectrum between them. One common classification of TD distinguishes affected infants based on the presence or absence of CS. In contrast, and as originally proposed by Langer et al. [1987: Am J Med Genet 3: 167-179], our data suggest that TD can be divided into at least two groups (TD1 and TD2) based on the presence of straight or curved femora. The variable presence of CS and severity of the radiologic and histologic findings in the other substitutions may be due to other genetic, environmental, or stochastic factors.