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tuberous sclerosis


Monday 15 December 2003

Digital slides

- Case 116 : Collagen and folliculocystic hamartoma in tuberous sclerosis

Definition: Tuberous sclerosis complex (TSC) is a multi-system genetic disorder typically known for lesions in the skin, kidneys, heart and brain. Tuberous sclerosis is a rare congenital disorder with an incidence of 1 in 6000 births. The classic triad is seizure, mental deficiency, and angiofibromas.

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.

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.

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.

Clinical synopsis

- skin

  • multiple hypomelanotic macules
  • facial angiofibromas
  • shagreen patches
  • periungueal fibromas
  • soft tissue fibromatosis (20108343)

- kidneys

  • angiomyolipomas (AMLs)
  • renal cysts
  • renal cell carcinomas

- heart
- cardaic rhabdomyomas (often associated with dysrhythmias, including Wolff-Parkinson-White syndrome)

- lung

- central nervous system (CNS)

  • 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.

- orofacial manifestations

  • fibrous hyperplasia
  • hemangioma
  • bifid uvula
  • cleft lip and palate
  • macroglossia
  • high arched palate
  • enamel defects
  • benign tumors of the jaws

- Simultaneous Cushing disease and tuberous sclerosis (16343106)

-  thyroid anomalies (8135291)

- tumor predisposition

  • facial angiofibromas or forehead plaques
  • shagreen patch (connective tissue nevus)
  • three or more hypomelanotic macules
  • nontraumatic ungula or periungual fibromas
  • soft tissue fibromatosis (20108343)
  • tongue-base hamartoma (11320836)
  • lymphangioleiomyomatosis (also known as lymphangiomyomatosis)
  • renal angiomyolipoma
  • cardiac rhabdomyoma
  • multiple retinal nodular hamartomas
  • cortical tuber
  • subependymal nodules
  • subependymal giant cell astrocytoma
  • pineal region giant cell astrocytoma (15881760)
  • confetti skin lesions (multiple 1 to 2 mm hypomelanotic macules)
  • gingival fibromas
  • multiple randomly-distributed pits in dental enamel
  • hamartomatous rectal polyps
  • multiple renal cysts
  • non-renal hamartomas
  • bone cysts
  • retinal achromic patch
  • cerebral white matter radial migration lines
  • thyroid papillary carcinoma of the thyroid (12608660)


Approximately 10 to 30% of cases of tuberous sclerosis are due to mutations in the TSC1 gene: the frequency of cases due to mutations in the TSC2 gene is consistently higher. TSC2 mutations are associated with more severe disease.

- 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)


- 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

- TSCs: TSC1 and TSC2


- 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


- 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

- Concurrent bilateral renal angiomyolipoma and renal cell carcinoma in a patient with tuberous sclerosis complex. Khallouk A, Ahallal Y, Doublali M, Tazi MF, Mellas S, El Fassi MJ, Farih MH. Rev Urol. 2009 Fall;11(4):216-8. PMID: 20111634

- Medullary thyroid carcinoma and tuberous sclerosis. Dicorato P, Calvanese A, Maiuolo A, D’Alessandri M, Grani G, Ruggieri M, Fumarola A. Endocr Pathol. 2009 Summer;20(2):141-4. PMID: 19424876

- Pancreatic somatostatinoma and tuberous sclerosis: case report of an exceedingly rare association. Sreenarasimhaiah J, Armstrong LA, Tang SJ, Barnett C. Gastrointest Endosc. 2009 Feb;69(2):379-81. PMID: 18672238