PTEN and Cowden syndrome 1: Patients who meet the clinical criteria for CS but do not demonstrate a mutation in the PTEN gene have been found to have germline mutations in SDHB, SDHC, and SDHD, resulting in “second hit” mutations that lead to heterozygous loss of PTEN. Hereditary pheochromocytoma and paraganglioma syndromes are also caused by these three genetic mutations.