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.