# Handbook of Genetic Counseling/Tuberous Sclerosis

Tuberous Sclerosis

## Contracting

* What have you been told about why you were referred?
* What questions or concerns would you like us to address today?

## 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.