Clinical Information

Germline variants in the PTEN gene are associated with a rare group of overlapping clinical syndromes collectively referred to as PTEN hamartoma tumor syndrome (PHTS). This includes Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome, Proteus syndrome, Proteus-like syndrome, and autism with macrocephaly.(1,2)

PHTS is inherited in an autosomal dominant manner.(1) Between 10% to 48% of individuals with PHTS have a de novo PTEN variant.(3) Affected individuals have an increased risk of cancer, including cancers of the breast, endometrium, thyroid, kidney, and colon.(1) Individuals with PHTS also may present with macrocephaly, vascular lesions, trichilemmomas, mucocutaneous papillomatous papules, lipomatosis, hemangiomatosis, and pigmented macules on the glans penis.(1) Dysplastic gangliocytoma of the cerebellum, also known as Lhermitte-Duclos disease, is another hamartomatous tumor associated with PHTS.(1) Intellectual disability, developmental delay, and autism are commonly seen in individuals with PHTS.(1)

Since it was reported that PTEN variants account for 10% to 20% of individuals with autism with macrocephaly, the American College of Medical Genetics and Genomics has recommended PTEN gene testing in individuals with both features.(4) The long-term clinical outcomes of individuals with PTEN-related autism with macrocephaly is not currently known.(1,2) As such, individuals with PTEN-related autism with macrocephaly should follow the same cancer screening recommendations provided for PHTS.(1,2)

The National Comprehensive Cancer Network provides recommendations regarding the medical management of individuals with PHTS.(5)