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