Hereditary tumor syndromes. Cutaneous manifestations and molecular pathogenesis of Gorlin and Cowden syndromes

Abstract

Several hereditary tumor syndromes are associated with characteristic skin lesions which may facilitate an early diagnosis. We summarize clinical features and recent progress in understanding the etiology and pathogenesis of two selected tumor syndromes, namely nevoid basal cell carcinoma syndrome (Gorlin syndrome) and Cowden syndrome. Both are autosomal dominantly inherited disorders. Nevoid basal cell carcinoma syndrome is characterized by the early onset of multiple basal cell carcinomas as as well as developmental defects and a predisposition for other benign and malignant tumors. The syndrome is caused by germline mutations in the PTCH tumor suppressor gene. Cowden syndrome is associated with pathognomonic mucocutaneous lesions, such as facial trichilemmomas, acral keratoses, and mucocutaneous papillomatosis. In addition, Cowden patients are predisposed to carcinomas of the thyroid, breast and endometrium. Cowden syndrome is caused by germline mutations in the PTEN tumor suppressor gene. Identification of the genes causing hereditary tumor syndromes as well as generation of genetically engineered mouse models have greatly advanced our understanding of the molecular pathogenesis of these diseases. Furthermore, novel pathogenesis-based pharmacological strategies are being developed that promise to improve prevention and therapy.