Cowden syndrome and the PTEN Hamartoma tumor syndrome: how to define rare genetic syndromes

Cowden syndrome (OMIM No. 158350) and Bannayan-Riley-Ruvalcaba syndrome (BRRS) (OMIM No. 153480) are autosomal dominant conditions described before the genetic testing era. The early reports of Cowden syndrome were by adult physicians and dermatologists who recognized a pattern of benign and malignant tumors affecting the breast and thyroid, accompanied by characteristic acral keratosis and trichilemmomas of the skin (1,2,3). BRRS was described by pediatricians and clinical geneticists, with the principle features being macrocephaly, delayed development, lipomata, hemangiomas, and vascular malformations, along with pigmented macules of the penis (4,5). Both conditions are caused by mutations in the PTEN gene (OMIM+601728) (6,7). There is no definite association between the type or position of mutation within the PTEN gene and the clinical presentation of the patient. Both conditions have been described in different members of the same family with the same mutations, and it is clear that meticulous examination reveals features of childhood-onset BRRS in adults presenting with the features of Cowden syndrome and vice versa. It is therefore generally accepted that they are one condition, with variable expression and age-related penetrance (8,9,10,11). Genetic heterogeneity has been reported with reports of Cowden-like patients(ie, those who do not fulfill criteria for PTEN hamartoma syndrome [PHTS]) with mutations in SDHB, SDHD, AKT, and PIK3CA, as well as hypermethylation of the promoter of the KLLN gene (12,13,14,15)