Purpose Age-adjusted cancer incidence and age-related penetrance studies have helped guide cancer risk assessment and management. PTEN Hamartoma-Tumor Syndrome (PHTS) is a term encompassing subsets of several clinical syndromes with germline mutations in the PTEN tumor suppressor gene. We conducted the first prospective study to clarify corresponding cancer risks to shed biological insights on human germline PTEN mutations, and to better inform current surveillance recommendations based on expert opinion. Methods A series of 3,399 individuals meeting relaxed International Cowden Consortium PHTS criteria were prospectively recruited; 368 individuals were found to have deleterious germline PTEN mutations. Age-adjusted standardized incidence ratio (SIR) calculations and genotype-phenotype analyses were performed. Results Elevated SIRs were found for carcinomas of the breast (25.4, 95%C.I. 19.8-32.0), thyroid (51.1, 38.1-67.1), endometrium (42.9, 28.1-62.8), colorectum (10.3, 5.6-17.4), and kidney (30.6, 17.8-49.4), and melanoma (8.5, 4.1–15.6). Estimated lifetime risks were, respectively, 85.2% (95%C.I. 71.4%-99.1%), 35.2% (19.7%-50.7%), 28.2% (17.1%-39.3%), 9.0% (3.8-%14.1%), 33.6% (10.4%–56.9%) and 6% (1.6%-9.4%). Promoter mutations were associated with breast cancer, while colorectal cancer was associated with nonsense mutations. Conclusion Lifetime risks for a variety of cancers, now extending to colorectal cancer, kidney cancer and melanoma, are increased in patients with PTEN mutations. The genotype-phenotype associations here may provide new insights on PTEN structure and function. We propose a comprehensive approach to surveillance of patients with PTEN mutations.

Purpose By incorporating major developments in genetics, ophthalmology, dermatology, and neuroimaging, to revise the diagnostic criteria for neurofibromatosis type 1 (NF1) and to establish diagnostic criteria for Legius syndrome (LGSS). Methods We used a multistep process, beginning with a Delphi method involving global experts and subsequently involving non-NF experts, patients, and foundations/patient advocacy groups. Results We reached consensus on the minimal clinical and genetic criteria for diagnosing and differentiating NF1 and LGSS, which have phenotypic overlap in young patients with pigmentary findings. Criteria for the mosaic forms of these conditions are also recommended. Conclusion The revised criteria for NF1 incorporate new clinical features and genetic testing, whereas the criteria for LGSS were created to differentiate the two conditions. It is likely that continued refinement of these new criteria will be necessary as investigators (1) study the diagnostic properties of the revised criteria, (2) reconsider criteria not included in this process, and (3) identify new clinical and other features of these conditions. For this reason, we propose an initiative to update periodically the diagnostic criteria for NF1 and LGSS.

CS/CS-like patients have elevated risks of follicular thyroid cancer due to PTEN pathogenic mutations and of papillary thyroid cancer from SDHx and KLLN alterations. Children presenting with thyroid cancer should be tested for PTEN mutations.