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Thanatophoric Dysplasia (TD) is a severe skeletal disorder that is lethal in the neonatal period. Two clinically defined TD subtypes have been classified: type I (TDI), characterized by micromelia with bowed femurs and, occasionally, by the presence of cloverleaf skull deformity of varying severity and type II (TDII), characterized by micromelia with straight femurs and a moderate to severe cloverleaf skull deformity. TD is caused by specific autosomal dominant mutations in the gene that codifies for the Fibroblast Growth Factor Receptor 3 (FGFR3). The mutations constitutively activate the tyrosine kinase activity of the receptor. As normally FGFR3 is a negative regulator of bone growth, the gain-of-function mutations associated to TD allow the activated receptor to send negative signals within the cells of the cartilage (chondrocytes), thus leading to the generalized disorganization of endochondral ossification at the bone growth plate. The estimated birth incidence is approximately 1/20,000 to 1/50,000 TDI being more frequent than TDII. Most individuals with TD die within the first few hours or days of life by respiratory insufficiency secondary to reduced thoracic capacity or compression of the brainstem. Currently, specific therapeutic regiments other than sustenance of symptoms do not exist. Prenatal diagnosis is available, both by ultrasonography and by molecular studies.
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