Atlas of Genetics and Cytogenetics in Oncology and Haematology

Home   Genes   Leukemias   Solid Tumors   Cancer-Prone   Deep Insight   Case Reports   Journals  Portal   Teaching   

X Y 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 NA

Tuberous sclerosis (TSC)

Written2002-06Julie Steffann, Arnold Munnich, Jean-Paul Bonnefont
INSERM U393, Groupe Hospitalier Necker-Enfants Malades, Tour Lavoisier 2, 149 rue de Sövres, 75743 Paris Cedex15, France

(Note : for Links provided by Atlas : click)


Other namesBourneville disease
Atlas_Id 10014
Genes implicated inTSC1   TSC2  
  • Frequency : 1/6000-1/10000 birth.
    First genetic cause of epilepsy associated with mental retardation = epiloia.
    2/3 of cases are sporadic, 1/3 are inherited.
  • Genetic heterogeneity : two genes, TSC1 and TSC2, account for the majority of cases.
    Somatic mosaicism has been reported in association with a milder form of the disease.
    Germinal mosaicism has been described and must be taken into account for genetic counselling.
  • Autosomal dominant with almost complete penetrance but variable expressivity.
  • Clinics

    Note Disability in TSC patients most often results from the involvement of brain. Two types of lesions are static (hamartias) ; cortical tubers, and subcortical heterotopic nodules, whereas subependymal nodules are often progressive (hamartoma), hence the term subependymal giant cell astrocytoma.
    Phenotype and clinics The definition of the tuberous sclerosis complex requires either two major features or one major feature plus two minor features.
  • Major features :
    - Facial angiofibromasor forehead plaque
    - Non traumatic ungual or periungual fibroma
    - Hypomelanotic macules (three or more)
    - Shagreen patch ( connective tissue nevus)
    - Multiple retinal nodular hamartomas
    - Cortical tuber
    - Subependymal nodule
    - Subependymal giant cell astrocytoma
    - Cardiac rhabdomyoma, single or multiple
    - Lymphangiomyomatosis
    - Renal angiomyolipoma
  • Minor features :
    - Multiple, randomly distributed pits in dental enamel
    - Hamartomatous rectal polyps
    - Bone cysts
    - Cerebral white matter radial migration lines
    - Gingival fibromas
    - Nonrenal hamartoma
    - Retinal achromic patch
    - " confetti " skin lesions
    - Multiple renal cysts
  • Neoplastic risk
  • Renal angiomyolipomas, often multiple and bilateral, (75% of children withTSC). Occasionnally (< 2-3%), turn into renal carcinomaonly later in life.
  • Cardiac rhabdomyomas, often congenital, tend to regress in infancy, remain identical in same size through out childhood and can then either again regress or progress (girls) in adolescence.
  • Brain tumors, (incidence 5-14%), are mostly (>90%) subependymal giant cell astrocytomas, or ependymomas.
  • Hamartomas also occur in liver, spleen, and various tissues.
  • Pulmonary lymphangiomyomatosis is a destructive lung disease characterized by a diffuse hamartomatous proliferation of smooth muscle cells in lungs.
  • Cytogenetics

    Inborn conditions Increased frequency of premature centromere disjonction (PCD) in cultured fibroblasts, especially for chromosome 3
    Cytogenetics of cancer No special feature

    Genes involved and Proteins

    Note Two genes are involved, TSC1 and TSC2.
    The patients with TSC1 mutations would have a milder form of the disease, compared to those with TSC2 mutations.
    Gene NameTSC1 (Tuberous Sclerosis 1)
    Location 9q34.13
    Note Accounts for about 50% of TSC patients
    Description 23 exons
    Note Tumor suppressor
    Description Hamartin and tuberin cohybridize in vivo. Hamartin is a growth inhibitory protein, affecting cell proliferation via deregulation of G1 phase, possibly by regulating cellular adhesion through ezrin-radixin-moiesin family proteins and the small GTP-binding protein RHO

    Gene NameTSC2 (tuberous sclerosis 2)
    Location 16p13.3
    Note Accounts for about 50% of TSC patients.
    Description 41 exons
    Note tumor suppressor
    Expression Fonctions as a GTPase activating protein which activates the Ras-related family of small GTP-binding proteins such as Rap1 and Rab5. Inhibits the G1/S transition and promotes entry to the G0 phase. The Eker rat, a naturally occuring animal model of TSC, has an autosomal dominant trait of renal cell carcinoma caused by a germline mutation in the rat TSC2 gene.
    Germinal Most TSC1 and TSC2 mutations are truncating mutations. Both large deletions and missense mutations are not uncommon at TSC2 locus, whereas most TSC1 mutations are small truncating lesions.
    Somatic Loss of heterozygosity has been described in some tumor types, such as angiomyolipomas, giant cell astrocytomas, or rhabdomyomas, but is rare in cortical tubers.


    Complete inactivation of the TSC2 gene leads to formation of hamartomas.
    Au KS, Hebert AA, Roach ES, Northrup H
    American journal of human genetics. 1999 ; 65 (6) : 1790-1795.
    PMID 10577937
    The natural history of cardiac rhabdomyoma with and without tuberous sclerosis.
    Bosi G, Lintermans JP, Pellegrino PA, Svaluto-Moreolo G, Vliers A
    Acta paediatrica (Oslo, Norway : 1992). 1996 ; 85 (8) : 928-931.
    PMID 8863873
    Apparent preferential loss of heterozygosity at TSC2 over TSC1 chromosomal region in tuberous sclerosis hamartomas.
    Carbonara C, Longa L, Grosso E, Mazzucco G, Borrone C, Garrè ML, Brisigotti M, Filippi G, Scabar A, Giannotti A, Falzoni P, Monga G, Garini G, Gabrielli M, Riegler P, Danesino C, Ruggieri M, Magro G, Migone N
    Genes, chromosomes & cancer. 1996 ; 15 (1) : 18-25.
    PMID 8824721
    Molecular genetic advances in tuberous sclerosis.
    Cheadle JP, Reeve MP, Sampson JR, Kwiatkowski DJ
    Human genetics. 2000 ; 107 (2) : 97-114.
    PMID 11030407
    Comprehensive mutation analysis of TSC1 and TSC2-and phenotypic correlations in 150 families with tuberous sclerosis.
    Jones AC, Shyamsundar MM, Thomas MW, Maynard J, Idziaszczyk S, Tomkins S, Sampson JR, Cheadle JP
    American journal of human genetics. 1999 ; 64 (5) : 1305-1315.
    PMID 10205261
    A germline insertion in the tuberous sclerosis (Tsc2) gene gives rise to the Eker rat model of dominantly inherited cancer.
    Kobayashi T, Hirayama Y, Kobayashi E, Kubo Y, Hino O
    Nature genetics. 1995 ; 9 (1) : 70-74.
    PMID 7704028
    Neuropathology of tuberous sclerosis.
    Mizuguchi M, Takashima S
    Brain & development. 2001 ; 23 (7) : 508-515.
    PMID 11701246
    Tuberous Sclerosis Consensus Conference: recommendations for diagnostic evaluation. National Tuberous Sclerosis Association.
    Roach ES, DiMario FJ, Kandt RS, Northrup H
    Journal of child neurology. 1999 ; 14 (6) : 401-407.
    PMID 10385849
    High rate of mosaicism in tuberous sclerosis complex.
    Verhoef S, Bakker L, Tempelaars AM, Hesseling-Janssen AL, Mazurczak T, Jozwiak S, Fois A, Bartalini G, Zonnenberg BA, van Essen AJ, Lindhout D, Halley DJ, van den Ouweland AM
    American journal of human genetics. 1999 ; 64 (6) : 1632-1637.
    PMID 10330349


    This paper should be referenced as such :
    Steffann, J ; Munnich, A ; Bonnefont, JP
    Tuberous sclerosis (TSC)
    Atlas Genet Cytogenet Oncol Haematol. 2002;6(4):314-315.
    Free journal version : [ pdf ]   [ DOI ]
    On line version :

    Other genes implicated (Data extracted from papers in the Atlas) [ 4 ]

    Genes FKBP8 MTOR TSC1 TSC2

    External links

    OrphanetTuberous sclerosis
    Other databaseTuberous sclerosis complex (GARD)
    Genes implicated inTSC1   [ Atlas ]   [ Entrez ]  [ LOVD ]  [ GeneReviews ]  
    Genes implicated inTSC2   [ Atlas ]   [ Entrez ]  [ LOVD ]  [ GeneReviews ]  

    REVIEW articlesautomatic search in PubMed
    Last year articlesautomatic search in PubMed

    © Atlas of Genetics and Cytogenetics in Oncology and Haematology
    indexed on : Fri Oct 1 16:52:51 CEST 2021

    Home   Genes   Leukemias   Solid Tumors   Cancer-Prone   Deep Insight   Case Reports   Journals  Portal   Teaching   

    For comments and suggestions or contributions, please contact us