Handbook of Genetic Counseling/Tuberous Sclerosis
Tuberous Sclerosis
Contracting
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Disease characteristics and Etiology
edit- 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
- TSC1
- 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
edit- 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
- Hypomelanotic macules (87-100%)
- 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
- Cardiac rhabdomyomas (47-67%)
- 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
- Lymphangioleiomyomatosis of lung (1-6%)
- 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
edit- 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
- Three classes
- 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
edit- 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
edit- 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
edit- 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
edit- 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
editThe information in this outline was last updated in 2001.