Background Cowden syndrome (CS) is associated with benign hamartomatous lesions and risks for thyroid, breast and endometrial cancers. Bannayan–Riley–Ruvalcaba syndrome is an allelic disorder characterised by macrocephaly, intestinal polyps, lipomas, and pigmented penile macules. Diagnostic criteria for CS are based on the presence of a range of clinical features. However, prior data on the component clinical features have been based primarily on compilations of cases reported before development of consensus diagnostic criteria.

Objective This study sought to determine the clinical features most predictive of a mutation in the largest single cohort of patients with clinical testing for PTEN mutations reported to date.

Methods Molecular and clinical data were reviewed on 802 patients referred for PTEN analysis by a single laboratory.

Results Deleterious mutations were found in 172 (21.4%) subjects. Among mutation carriers significant differences from previous reports were found for the frequencies of several clinical features, including macrocephaly, uterine fibroids, benign breast disease, and endometrial cancer. Logistic regression analyses indicated that female mutation carriers were best identified by the presence of macrocephaly, endometrial cancer, trichilemmomas, papillomatous papules, breast cancer, benign thyroid disease, and benign gastrointestinal (GI) lesions. For males, the most discriminating features were macrocephaly, lipomas, papillomatous papules, penile freckling, benign GI lesions, and benign thyroid disease. Age related differences were also identified.

Conclusion The mutation frequency in patients meeting CS diagnostic criteria (34%) was significantly lower than previously reported, suggesting a need for reevaluation of these criteria. A mutation prediction model has been developed which can help identify patients appropriate for PTEN testing in clinical practice.