Handbook of Genetic Counseling/Tuberous Sclerosis

Tuberous Sclerosis

Contracting

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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%)

Testing

• 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

Surveillance/Management/Treatment

• 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

Resources

• Tuberous Sclerosis Alliance

(800) 225-6872

www.tsalliance.org

• Autism Society of America

(301) 657-0881

www.autism-society.org

• Epilepsy Foundation of Greater Cincinnati

(513) 721-2905

www.epilepsyfoundation.org

References

• 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

Notes

The information in this outline was last updated in 2001.