The Proteus syndrome (PS) and the Bannayan-Zonana syndrome (BZS) both have multiple hamartomata as prominent features. Hemihypertrophy, macrodactyly, exostoses, skin lesions, scoliosis, and sporadic occurrence are seen in PS, whereas patients with BZS have macrocephaly and related craniofacial findings. BZS has been observed in families as an autosomal dominant trait. Although the two syndromes can be distinguished in most patients, there are features in common to both that may pose a diagnostic dilemma in an isolated case. We report the case of a 3-year-old girl with macrocephaly, macrodactyly, and superficial and intra-abdominal hamartomata who illustrates the problem of differentiating between PS and BZS. We compare this patient and another recently reported patient with other published cases of PS and BZS. Patients with PS, in general, show more extensive systemic involvement, including skeletal and cutaneous manifestations. Macrocephaly, seen in all reported patients with BZS, is also found in 14% of patients with PS. Overlap among syndromes which include hamartomata as prominent features suggests that they might be etiologically or pathogenetically related. The present case also illustrates the usefulness of imaging techniques in the diagnosis of mixed mesodermal hamartomata.