Phenotypic variability at the TGF-β1 locus in Camurati-Engelmann disease

Camurati-Engelmann disease (CED) [OMIM 131300] is an autosomal dominant sclerosing bone dysplasia recently ascribed to mutations of the transforming growth factor (TGF-beta1) gene on chromosome 19q13.1q13.3. Five mutations consistently located in the TGF-beta1 propeptide have been hitherto identified in 21 families. Here, we report on TGF-beta1 mutations in one Australian and six European families. Three distinct mutations were identified among seven families: namely, R218H (family 1), R218C (families 2, 6, 7) and C225R (families 3, 4, 5). The three mutations identified in our pedigrees have been previously observed in families of Japanese and Israeli origin and the R218C appears to be the most prevalent mutation worldwide (17/28 reported families). No obvious correlation between the nature of the mutations and the severity of the clinical manifestations could be established, but a marked intrafamilial clinical variability was observed, supporting incomplete penetrance of CED. Interestingly, the polymorphisms in the TGF-beta1 gene showed no correlation with the severity of the disease. We conclude that CED is a clinically variable condition and that this clinical variability is not accounted for by polymorphisms at the TGF-beta1 locus.