Tuberous sclerosis (TSC)

2002-06-01   Julie Steffann , Arnold Munnich , Jean-Paul Bonnefont 

INSERM U393, Groupe Hospitalier Necker-Enfants Malades, Tour Lavoisier 2, 149 rue de Sövres, 75743 Paris Cedex15, France



Tuberous sclerosis (TSC)


Bourneville disease , Epiloia


  • 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.
  • Omim

    191092 , 191100




    805 Tuberous sclerosis




    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


    Inborn condition

    Increased frequency of premature centromere disjonction (PCD) in cultured fibroblasts, especially for chromosome 3

    Cancer cytog

    No special feature

    Genes involved and Proteins


    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.


    Accounts for about 50% of TSC patients


    23 exons


    Tumor suppressor


    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


    Accounts for about 50% of TSC patients.


    41 exons


    tumor suppressor


    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.


    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.


    Loss of heterozygosity has been described in some tumor types, such as angiomyolipomas, giant cell astrocytomas, or rhabdomyomas, but is rare in cortical tubers.

    To be noted


    120735 TSC1120466 TSC2


    Pubmed IDLast YearTitleAuthors
    105779371999Complete inactivation of the TSC2 gene leads to formation of hamartomas.Au KS et al
    88638731996The natural history of cardiac rhabdomyoma with and without tuberous sclerosis.Bosi G et al
    88247211996Apparent preferential loss of heterozygosity at TSC2 over TSC1 chromosomal region in tuberous sclerosis hamartomas.Carbonara C et al
    110304072000Molecular genetic advances in tuberous sclerosis.Cheadle JP et al
    102052611999Comprehensive mutation analysis of TSC1 and TSC2-and phenotypic correlations in 150 families with tuberous sclerosis.Jones AC et al
    77040281995A germline insertion in the tuberous sclerosis (Tsc2) gene gives rise to the Eker rat model of dominantly inherited cancer.Kobayashi T et al
    117012462001Neuropathology of tuberous sclerosis.Mizuguchi M et al
    103858491999Tuberous Sclerosis Consensus Conference: recommendations for diagnostic evaluation. National Tuberous Sclerosis Association.Roach ES et al
    103303491999High rate of mosaicism in tuberous sclerosis complex.Verhoef S et al