Hyperdontia, also known as supernumerary teeth, is a developmental anomaly of tooth number. Supernumerary teeth can be found single or multiple, unilateral or bilateral, erupted or impacted, in one or both jaws. Hyperdontia can occur as an isolated trait or as part of genetic syndromes. Objective: to identify the genetic cause of the clinical heterogeneity of hyperdontia as observed in our cases. Patients and Methods: investigation of hyperdontia was carried out on 58 patients; the diagnosis of hyperdontia has been made by oral and radiographic examinations; based on the number affected teeth we classified the patients in three groups: patients with single supernumerary tooth, patients with two supernumerary teeth and multiple extra teeth; family study, cytogenetic and molecular analysis were performed. Results:55 subjects presented hyperdontia as an isolated trait ; 3 patients were affected by genetic syndromes having hyperdontia as an associated findings; one supernumerary tooth occurred in 37 cases; 1 case expressed single supernumerary tooth in association with beta-thalassemia; the isolated form of hyperdontia occurred sporadic or familial; the affected members within a family often exhibited variable expression of hyperdontia; multiple supernumerary teeth were found in association with cleidocranial dysplasia. The analysis of the entire RUNX2/CBFA1 coding sequence by PCR amplification identified the mutations R225W. Concomitant hyperdontia/hypodontia was found in 1 case. Conclusions: clinical heterogeneity in hyperdontia could be explained by genetic heterogeneity. Factors as different alleles of a single gene, mutations in different genes, modifier genes and environmental conditions play a role in the abnormal tooth morphogenesis.