Cherubism is an autosomal dominant inherited syndrome characterized by excessive bone degradation of upper and lower jaw and its replacement with large amounts of fibrous tissue, which causes a characteristic facial swelling. A correlation with a mutation in the gene SH3BP2 has been previously demonstrated, but a model for its pathogenesis is not yet available. Here we describe a novel mutation in an aggressive case of cherubism located in the pleckstrin homology domain (PH) of the SH3BP2.