MOLECULAR, RADIOLOGIC, AND HISTOPATHOLOGIC CORRELATIONS IN THANATOPHORIC DYSPLASIA

Various mutations in the fibroblast growth factor receptor 3 (FGFRS) g ene have recently been reported in thanatophoric dysplasia (TD), We ex amined the clinical, radiographic, and histologic findings in 91 cases from the International Skeletal Dysplasia Registry and correlated the m with the specific FGFR3 mutation. Every case of TD examined had an i dentifiable FGFR3 mutation. Radiographically, all of the cases with th e Lys650Glu substitution demonstrated straight femora with craniosynos tosis, 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, bu t cases with the Lys650Glu substitution had better preservation of the growth plate. Cases with the Tyr373Cys substitution tended to have mo re severe radiographic manifestations than the Arg248Cys cases, but th ere was overlap in the phenotypic spectrum between them. One common cl assification of TD distinguishes affected infants based on the presenc e 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 presen ce of straight or curved femora, The variable presence of CS and sever ity of the radiologic and histologic findings in the other substitutio ns may be due to other genetic, environmental, or stochastic factors. (C) 1998 Wiley-Liss, Inc.