Tuberous sclerosis: a syndrome of incomplete tumor suppression

Todd McCall M.D., Steven S. Chin M.D., Ph.D., Karen L. Salzman M.D., and Daniel W. Fults M.D.
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  • Departments of Neurosurgery, Pathology, and Radiology, University of Utah School of Medicine, Salt Lake City, Utah
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Tuberous sclerosis (TS) is a congenital neurocutaneous syndrome (or phacomatosis) characterized by widespread development of hamartomas in multiple organs. For affected individuals, neurological and psychiatric complications are the most disabling and lethal features. Although the clinical phenotype of TS is complex, only three lesions characterize the neuropathological features of the disease: cortical tubers, subependymal nodules, and subependymal giant cell astrocytomas. The latter is a benign brain tumor of mixed neuronal and glial origin. Tuberous sclerosis is caused by loss-of-function mutations in one of two genes, TSC1 or TSC2. The normal cellular proteins encoded by these genes, hamartin and tuberin, respectively, form a heterodimer that suppresses cell growth in the central nervous system by dampening the phosphatidylinositol 3–kinase signal transduction pathway. The authors review the clinical and neuropathological features of TS as well as recent research into the molecular biology of this disease. Through this work, investigators are beginning to resolve the paradoxical findings that malignant cancers seldom arise in patients with TS, even though the signaling molecules involved are key mediators of cancer cell growth.

Abbreviations used in this paper:ATP = adenosine 5′-triphosphate; IGF = insulin-like growth factor; IRS-1 = insulin receptor substrate–1; MR = magnetic resonance; mRNA = messenger RNA; mTOR = mammalian target of rapamycin; PIP2 = phosphatidylinositol 4,5-bisphosphate; PIP3 = phosphatidylinositol 3,4,5-trisphosphate; PI3K = phosphatidylinositol 3–kinase; SEGA = subependymal giant cell astrocytoma; SEN = subependymal nodule; TS = tuberous sclerosis; TSC = TS complex.

Tuberous sclerosis (TS) is a congenital neurocutaneous syndrome (or phacomatosis) characterized by widespread development of hamartomas in multiple organs. For affected individuals, neurological and psychiatric complications are the most disabling and lethal features. Although the clinical phenotype of TS is complex, only three lesions characterize the neuropathological features of the disease: cortical tubers, subependymal nodules, and subependymal giant cell astrocytomas. The latter is a benign brain tumor of mixed neuronal and glial origin. Tuberous sclerosis is caused by loss-of-function mutations in one of two genes, TSC1 or TSC2. The normal cellular proteins encoded by these genes, hamartin and tuberin, respectively, form a heterodimer that suppresses cell growth in the central nervous system by dampening the phosphatidylinositol 3–kinase signal transduction pathway. The authors review the clinical and neuropathological features of TS as well as recent research into the molecular biology of this disease. Through this work, investigators are beginning to resolve the paradoxical findings that malignant cancers seldom arise in patients with TS, even though the signaling molecules involved are key mediators of cancer cell growth.

Abbreviations used in this paper:ATP = adenosine 5′-triphosphate; IGF = insulin-like growth factor; IRS-1 = insulin receptor substrate–1; MR = magnetic resonance; mRNA = messenger RNA; mTOR = mammalian target of rapamycin; PIP2 = phosphatidylinositol 4,5-bisphosphate; PIP3 = phosphatidylinositol 3,4,5-trisphosphate; PI3K = phosphatidylinositol 3–kinase; SEGA = subependymal giant cell astrocytoma; SEN = subependymal nodule; TS = tuberous sclerosis; TSC = TS complex.

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Contributor Notes

Address reprint requests to: Daniel W. Fults, M.D., Department of Neurosurgery, 30 North 1900 East, Salt Lake City, Utah 84132-2303. email: daniel.fults@hsc.utah.edu.

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