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%)

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.