Hamartomas and tubers from defects in hamartin-tuberin

Abstract

her brain as well as in numerous other organs. 1 In time, additional patients with this inherited disease were studied and found to have benign tumors in virtually every organ, including the brain (cortical tubers, subependymal nodules, and giant cell astrocytomas), eyes (retinal hamartomas), kidneys (angiomyolipomas, cysts), heart (cardiac rhabdomyomas), lungs (lymphangioleiomyomatosis), and skin. Recent molecular investigations have revealed that this potpourri of seemingly unrelated findings, called tuberous sclerosis complex (TSC),results from a dysregulated signaling pathway. These discoveries have profound clinical implications. The skin is paradigmatic for TSC. TSC presents a variable clinical picture, and the skin lesions are no less variable. TSC skin lesions range from subtle to disfiguring. A patient may have one or several types of skin lesions, and each type may be single or multiple. Many of the skin and internal tumors in TSC are hamartomas that are highly vascular. Both skin tumors and internal tumors occur in characteristic locations with typical ages of onset. Proclivity of skin tumors for certain regions of the body is indicated by the names of lesions, such as facial angiofibromas, periungual fibromas, and forehead plaques. In contrast, hypopigmented macules seemingly occur at random locations, and exhibit differences in size and shape (ash leaf vs confetti-like), location (hypopigmented macule vs poliosis), and extent. Hypomelanotic macules are typically present at birth or appear during early infancy. Angiofibromas usually develop at about 3 to 5 years, while periungual fibromas emerge in the teen years or later. 2 Skin lesions may be a presenting feature and can form the basis for the diagnosis of TSC. Among the diagnostic criteria, mucocutaneous lesions comprise 4 major features (angiofibromas or forehead plaque, subungual or periungual fibromas, hypomelanotic macules, and the shagreen patch) and 3 minor features (confetti-like hypopigmentation, gingival fibromas, and multiple dental pits). 3 These 1998 criteria were modified from earlier versions to accommodate recent observations. Multiple facial angiofibromas are no longer considered pathognomonic for TSC, as they are also observed in multiple endocrine neoplasia type 1. More than 3 hypomelanotic macules must be observed to qualify as a major feature of TSC, because solitary lesions are commonly observed in the general population. Finally, consideration is given to the fact that single ungual fibromas may occur in the general popu