tuberous sclerosis
MIM.191100
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Tuberous sclerosis complex (TSC) is an autosomal dominant condition whose signs and symptoms may vary from a few hypopigmented skin spots (ash-leaf spots) and angiofibroma (adenoma sebaceum) to epilepsy, severe mental retardation, renal failure, hamartomas in different organs, and only rarely malignant neoplasms.
Definition: Tuberous sclerosis complex (TSC) is a multi-system genetic disorder typically known for lesions in the skin, kidneys, heart and brain.
Disease-causing mutations in the TSC1 or TSC2 gene result in constitutive activation of the highly conserved mTOR signal transduction pathway, which regulates cell growth, proliferation, and metabolism.
The disorder has a birth incidence of 1:6 000; it is about twice as common as Huntington?s disease and three times as common as Williams Syndrome.
It is associated with mutations in either the TSC1 gene (9q34) or the TSC2 gene (16p13.3). TSC occurs as a spontaneous mutation in 70% of cases and is inherited in an autosomal-dominant fashion in the remaining 30% of cases.
Clinical synopsis
In the skin, the diagnostic features include multiple hypomelanotic macules, facial angiofibromas, shagreen patches and ungual fibromas. Renal abnormalities include angiomyolipomas (AMLs) and renal cysts, and cardiac features include rhabdomyomas often associated with dysrhythmias, including Wolff-Parkinson-White syndrome. A significant proportion of women with TSC have lymphangioleiomyomatosis (LAM) of the lung.
The central nervous system (CNS) is the organ system most consistently involved in TSC. More than 90% of individuals with TSC have radiologically detectable structural abnormalities, and almost all have some degree of functional CNS manifestation. One of the most striking features of the CNS manifestations is, however, the great variability observed. Some individuals are profoundly impaired and have severe, intractable seizures, autism and challenging behaviours, whereas others are extremely able and lead active, normal lives without any apparent impairment due to TSC
Etiology
Locus TSC1 (MIM.605284) at 9q34
Locus TSC2 (MIM.191092) at 16p13.3
Locus TSC3 at 12q14 (MIM.191091)
Locus TSC4 (MIM.191090)
The TSC1-TSC2 complex functions as GTPase activating protein against Rheb - a Ras-like small GTPase, which in turn regulates TOR signaling in nutrient-stimulated cell growth.
Tumoral predisposition
malignant pancreatic endocrine tumor (14508401)
Synopsis
renal angiomyolipoma
renal cell carcinoma
pulmonary lymphangiomyomatosis
renal cystic disease (contiguous gene deletion syndrome involving TSC2 and PKD1 on chromosome 16)
- unilateral renal cystic disease (16396832)
- diffuse bilateral renal cystic disease
See also
References
Lee L, Sudentas P, Dabora SL. Combination of a rapamycin analog (CCI-779) and interferon-gamma is more effective than single agents in treating a mouse model of tuberous sclerosis complex. Genes Chromosomes Cancer. 2006 Oct;45(10):933-44. PMID: 16845661
Reviews
Crino PB, Nathanson KL, Henske EP. The tuberous sclerosis complex. N Engl J Med. 2006 Sep 28;355(13):1345-56. PMID: 17005952
Pan D, Dong J, Zhang Y, Gao X. Tuberous sclerosis complex: from Drosophila to human disease. Trends Cell Biol. 2004 Feb;14(2):78-85. PMID: 15102439
Henske EP. Metastasis of benign tumor cells in tuberous sclerosis complex. Genes Chromosomes Cancer. 2003 Dec;38(4):376-81. PMID: 14566858