What is Tuberous Sclerosis Complex (TSC)?
- Rare autosomal dominant, multi-systemic disease causing benign tumors to grow in brain, kidneys, heart, eyes, lungs, and skin.
- 1/5,000-1/10,000 live births affected by TSC.
- Initially named for the characteristic tuber or potato-like growths seen in the brain.
- Common manifestations include seizures, developmental delay, behavior problems, skin abnormalities, kidney disease.
- TSC is described as a genetic disease, despite the fact that only 30% of the cases are familial.
- Prevalence of 25,000 to 40,000 patients in USA, and 1 to 2 million worldwide.
- TSC has equal in incidence in all races and both genders.
- Clinical features associated with TSC usually show within the first year of life; however, some may be subtle and insideious in nature, delaying diagnosis until much later.
- Mutations in TSC1 or TSC2 (chromosome 9) are known causes for TSC.
- Hamartin (TSC1) and tuberin (TSC2) are proteins that are missing in the disease leading to unregulated loss of tumor suppression.
- Hamartin and tuberin can be found in the cells of many different organs, thus explaining tumor presentation all over the body.
- Genetic mutations can present in several ways:
- Genetic autosomal dominant pattern- 100% penetrance 30%
- Sporadic mutations 70%
- Gonadal mosaicism- RARE
A young patient with tuberous sclerosis showing facial angiofibromas in characteristic butterfly pattern
One (useful?) mnemonic for the manifestations of tuberous sclerosis: HAMARTOMA
Mental retardation (now properly referred to as intellectual disability)
Angiomyolipoma (of kidney)
-Learning disability (50%)- autism, ADHD
-Glioneuronal hamartomas (cortical tubers), subependymal nodules, subependymal giant cell astrocytomas
-Mass effect symptoms, such as hydrocephalus and papilledema
-Seizures or infantile spasms. An example can be found HERE.
-Angiomyolipomas (60-80%), renal cysts
-Renal cell carcinoma (rare)
-Lymphangioleiomyomatosis (lung parenchyma replacement with cysts)
-Dermatologic sign= 95% of TSC
-Facial angiofibromas, periungual fibromas, hypomelanic macules, forehead plaques, Shagreen patches
-Minimal to no risk of malignant transformation of skin lesions
-Skin lesions tend to increase in size and number through puberty, and then tend to stabalize over time
-Astrocytic hamartomas (retinal)
-Coloboma, angiofibromas of eyelids, papilledema
The most important presentation is infantile spasms (seizures), but remember that many TSC cases can be asymptomatic and do not present until later in their course. However, the only definitive method of diagnosis is through genetic sequencing and the presence of mutations on TSC1 and TSC2. Imaging is also important in assessing the extent of organ invovlement.
Vogt's Triad= classical diagnostic triad < 50% of patients
- Seizures (80%)
- Intellectual disability
- Facial angiofibromas
(See diagnostic criteria from TSC Alliance site)
Unfortunately there is no cure for TSC. Treatment is provided on a symptom basis. Seizures can be controlled with antiepileptics, surgery may be considered for neurologic and dermatologic lesions. Severe cases may lead to developmental delay.
Newer: Recent study of Rapamycin (block mTOR activity) in animal models and preliminary clinical trials shows promising outcome.
Prognosis in this disease depends on severity of symptoms. The most mild cases have great prognoses, whereas the most severe cases cause profound disability. Most can expect normal life expectancy with medical care.
Leading causes of death:
Renal disease, brain tumor, lung involvement, status epilepticus
- Curatolo P. et al. Tuberous Sclerosis Complex: A review of Neurological Aspects. European Journal of Paediatric Neurology 2002
- Crino P.B. et al. The Tuberous Sclerosis Complex. NEJM 2006
- Kumar, V, Abbas, A K, Aster, J C. Robins and Cotran Pathologic Basis of Disease. 9th edition. 2015
- National Institutes of Health: Medline Plus Medical Encyclopedia. 9/11/2014 https://medlineplus.gov/ency/article/000787.htm
- Owens, J and Bodensteiner, J B. Tuberous sclerosis complex: Genetics, clinical features, and diagnosis. UpToDate.com. Jun 27, 2016.
- PrimeHealthChannel. Tuberous Sclerosis. http://www.primehealthchannel.com/tuberous-sclerosis.html
- Radhakrishnan, R, Verma, S. Clinically Relevant Imaging in Tuberous Sclerosis. Journal of Clinical Imaging Science. 2011. 1:39
- Staley B.A. et al. Tuberous Sclerosis Complex: Diagnostic Challenges, Presenting Symptoms, and Commonly Missed Signs. Pediatrics 2011
- Tuberous Sclerosis Alliance. What is TSC? http://www.tsalliance.org/pages.aspx?content=2