Handbook of Genetic Counseling/Tuberous Sclerosis

Tuberous Sclerosis


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Disease characteristics and Etiology

  • Genetic disorder that causes tumors to form in such organs as brain, eyes, heart, kidneys, skin, and lungs
  • Autosomal dominant inheritance
    • 2/3 of affected individuals have new mutations
    • Recurrence risks
      • If one parent affected, each pregnancy has 50% chance of inheriting mutation
      • If neither parent affected, recurrence risk is 1-2% to account for possible germline mosaicism
    • High mutation rate estimated at 1/25,000
    • Penetrance 100%
  • Two genes have been implicated
    • TSC1
      • Locus 9q34
      • Gene product is hamartin
    • TSC2
      • Locus 16p13
      • Gene product is tuberin
    • Functions not fully understood but have tumor suppressor function
      • Form heterodimers so may act together
      • Regulate cell proliferation
  • Incidence is about 1 in 6,000 live births
    • 50,000 affected in United States
    • More than 100,000 affected worldwide
    • Affects both sexes, all races and ethnic groups

Clinical Features and Natural History

  • Extreme variability both among and within families involving any organ system
  • Skin (100%) - don't result in serious medical problems
    • Hypomelanotic macules (87-100%)
      • On any part of the body in any shape, including ash-leaf spots
      • Can be seen using a Wood's lamp
    • Facial angiofibromas (47-90%)
      • Typically appear across cheeks and nose
      • May be present at birth or 4-5 years of age
    • Shagreen patches (20-80%)
      • Thickened and elevated pebbly skin
      • Found on lower back or nape of neck
    • Fibrous facial plaques
    • Ungual fibromata (17-87%)
      • Small, wart-like tumors around or under fingernails and toenails
      • Usually do not appear until later in life
  • Central Nervous System
    • Lead to most morbidity and mortality
    • Subependymal glial nodules (90%)
      • Develop in walls of ventricles that contain cerebrospinal fluid
      • Calcification occurs in first few years of life so can be detected on CT
      • Not directly responsible for neurological problems
    • Cortical or subcortical tubers (70%)
      • Small areas on cortex that develop abnormally
      • May be cause of seizures
      • Cortical tuber count on MRI may predict severity of cerebral dysfunction (more than 7 in moderately to severely affected patients)
    • Subependymal giant cell astrocytomas (6-14%)
      • Usually do not occur in young children and chance for growth decreases after age 20
      • Can become large enough to block flow of fluid in ventricles causing nausea, vomiting, headaches, changes in appetite, behavior, and mood
      • Brain imaging should be done every 1-3 years
    • Seizures/epilepsy (60-90%)
      • Can cause infantile spasm/hypsarrhtyhmia syndrome
      • Early in life may consist of brief head nodding or staring
      • May occur less often or cease in older children and adults
      • EEG and documentation of what seizures are like is important
    • Developmental delay or mental retardation (50-65%)
      • Leading cause of premature death in TS is complications of severe mental retardation (32%)
      • Close related with age of child at onset, frequency, duration, and severity of seizures
      • Children may regress if loss of seizure control occurs
    • Psychiatric and behavioral problems
      • Aggression, sudden rage, hyperactivity, attention deficit, obsessive-compulsive behaviors, repetitive behaviors
      • Linked with autism
      • Occasionally may be diagnosed with schizophrenia, bipolar disorder, depression
  • Kidneys
    • Renal disease is second leading cause of early death (28%) but complications do not occur until 2nd or 3rd decade of life
    • 80% of children have renal lesion by age 11
      • At diagnosis children should have baseline ultrasound, MRI, or CT
      • Repeat every 1-3 years
    • Benign angiomyolipoma (70%)
      • Less than 1% can become malignant
      • Can cause life threatening bleeding
    • Epithelial cysts (20%)
    • Oncocytoma (<1%) and renal cell carcinoma (<1%)
  • Heart
    • Cardiac rhabdomyomas (47-67%)
      • Form in infancy and disappear with time
      • Benign tumors but can cause blockage and death if severe
    • Children should have EKG to check for these problems
  • Lung
    • Lymphangioleiomyomatosis of lung (1-6%)
      • Degenerative cystic disease of lung
      • May progress to respiratory failure or death
    • Primarily affects women between ages of 20 and 40 years
  • Eye (75%)
    • Hamartomas or achromic (hypopigmented regions)
    • Rarely cause vision loss or problems
    • Opthalmoscopy with pupils dilated may help diagnose TS in children
  • Liver, pancreas, and other organs may develop benign cysts later in life
  • Pits in both baby and adult teeth (90%)


  • Diagnosis based on clinical findings
    • Three classes
      • Definite TSC - 2 major features or 1 major plus 2 minor features
      • Probably TSC - 1 major feature plus 1 minor feature
      • Possible TSC - 1 major feature or 2 or more minor features
    • Many of findings are nonspecific and may be isolated or associated with other syndromes
    • Major features
      • Facial angiofibromas or forehead plaque
      • Non-traumatic ungual or periungual fibromas
      • Three or more hypomelanotic macules
      • Shagreen patch
      • Multiple retinal nodular hamartomas
      • Cortical tuber
      • Subependymal nodule
      • Subependymal giant cell astrocytoma
      • Cardiac rhabdomyoma
      • Lymphangiomyomatosis
      • Renal angiomyolipoma
    • Minor features
      • Multiple 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
  • Molecular genetic testing
    • Available on a research basis for TSC1 and TSC2
    • Between 60-80% of families have identifiable mutation
    • Clinical testing is available for families who already have a mutation identified by research testing
  • Prenatal testing
    • DNA based testing possible for families at 50% risk with known gene mutation
    • High resolution ultrasound looking for tumors - unknown sensitivity


  • Patients undergo extensive initial evaluation to establish diagnosis
  • Patients require routine follow-up evaluations
    • Renal, cranial, chest CT or MRI
    • EEG for seizure management
    • Neurodevelopmental and behavioral evaluations
    • EKG if needed
  • Treat specific complications as needed

Psychosocial Issues

  • Guilt over new diagnosis, fear for child's future
  • Frustration over not being able to predict natural history
  • Burden of dealing with a child with serious health and behavioral problems
  • Frightening experience watching child have a seizure
  • Lifetime management


  • Tuberous Sclerosis Alliance
(800) 225-6872
  • Autism Society of America
(301) 657-0881
  • Epilepsy Foundation of Greater Cincinnati
(513) 721-2905


  • Mueller RF. "Tuberous Sclerosis." Management of Genetic Syndromes (2001): 437-457.
  • "My Child has Tuberous Sclerosis: A Brochure for Parents." Tuberous Sclerosis Alliance.
  • Northrup H, and Au KS. "Tuberous Sclerosis Complex." GeneReviews. www.geneclinics.org



The information in this outline was last updated in 2001.