Tuberous Sclerosis: A Rare Cause of Benign Tumors

Brain tumor
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Tuberous sclerosis (aka tuberous sclerosis complex) is a rare genetic disease that causes benign tumors to grow in various organ systems, including the brain, kidneys, heart, lungs, eyes, liver, pancreas, and skin. These tumors can result in developmental delay, seizures, kidney disease and more; however, prognosis ultimately depends on the extent of tumor dissemination or spread. Ultimately, many with the condition go on to live healthy lives.

How Common Is Tuberous Sclerosis?

Because tuberous sclerosis is pretty rare, it’s hard to pin down its true frequency. It’s estimated that this disease affects between 25,000 and 40,000 Americans and between one and two million people worldwide.

What Does 'Tuberous Sclerosis' Mean?

With tuberous sclerosis, tubers or potato-like tumors grow in the brain. These growths eventually become calcified, hardened, and sclerotic. Tuberous sclerosis was discovered more than 100 years ago by a French physician and was once known by two other names: epiloia or Bourneville's disease.

How Is Tuberous Sclerosis Inherited?

Tuberous sclerosis can be inherited in an autosomal dominant fashion. With autosomal dominant diseases, only one parent needs to have a copy of the mutated gene to pass the illness down to a son or daughter. Alternatively—and more commonly—tuberous sclerosis can stem from a spontaneous or sporadic mutation in the affected individual, with neither parent carrying the gene mutation responsible for causing tuberous sclerosis.

Tuberous sclerosis is caused by a gene mutation in either TSC1 or TSC2, which encodes hamartin or tuberin, respectively. (TSC1 is located on chromosome 9, and TSC2 is located on chromosome 16.) Furthermore, because the TSC1 gene is next to the PKD1 gene—thus increasing the likelihood of both genes getting affected—many people who inherit tuberous sclerosis also inherit autosomal dominant polycystic kidney disease (ADPKD).

Like tuberous sclerosis, autosomal dominant polycystic kidney disease causes tumors to grow in the kidneys.

In terms of mechanics, TSC1 and TSC2 do their damage by coding for hamartin or tuberin that ends up clumping into a protein complex. This protein complex deposits at the base of cilia and interferes with intracellular signaling, which is mediated by the enzyme (protein kinase) mTOR. By interfering with mTOR, cell division, replication and growth are affected, and abnormal growth of tumors results. Interestingly, scientists are currently trying to develop mTOR inhibitors that could be used as therapy for tuberous sclerosis.

What Are the Symptoms of Tuberous Sclerosis?

Tuberous sclerosis is a complex and thus manifests as symptoms involving various organ systems. Let’s take a look at effects on four specific organ systems: the brain, the kidneys, the skin and the heart.

Brain involvement. Tuberous sclerosis causes three types of tumors in the brain: (1) cortical tubers, which typically occur on the surface of the brain but can develop deeper in the brain; (2) supependymal nodules, which occur in the ventricles; and (3) supependymal giant-cell astroytomas, which stem from supependymal nodules and block the flow of fluid in the brain, thus resulting in a build-up in brain pressure leading to headaches and blurred vision.

Brain pathology secondary to tuberous sclerosis typically is the most damaging consequence of this disease. Seizures and developmental delays are common among those with this illness.

Kidney involvement. Very rarely does tuberous sclerosis result in chronic kidney disease and kidney failure; on urinalysis, urine sediment is often unremarkable and proteinuria (levels of protein in the urine) is mild to minimal. (People with more severe kidney disease can “spill” or lose protein in the urine.)

Instead, kidney signs and possible symptoms in those with tuberous sclerosis involve the growth of tumors called angiomyolipomas. These tumors occur in both kidneys (bilateral) and are usually benign, although if they get big enough (greater than 4 centimeters in diameter), they can bleed and will need to be surgically removed.

Of note unlike polycystic kidney disease, tuberous sclerosis can increase the risk of developing renal cell carcinoma (AKA kidney cancer). People with tuberous sclerosis should be regularly screened using diagnostic imaging to check for the development of kidney cancer.

Skin involvement. Nearly all people with tuberous sclerosis present with skin manifestations of the disease. These lesions include the following:

  • hypomelanotic macules (“ash leaf spots” which are patches on the skin that lack pigment and thus are lighter than surrounding skin)
  • shagreen patch (focal leathery thickening of the skin)
  •  “confetti” lesions
  • fibrous facial plaque
  • facial angiofibromas
  • ungual fibromas
  • adenoma sebaceum

Although these skin lesions are benign, or noncancerous, they can result in disfigurement, which is why they can be surgically removed.

Heart involvement. Infants born with tuberous sclerosis often present with heart tumors called rhabdomyomas. In most infants, these tumors don’t cause any problems and shrink with age. However, if the tumors get big enough, they can block circulation.

Treatment of Tuberous Sclerosis

There is no specific cure for tuberous sclerosis. Instead, this complex is treated symptomatically. For instance, antiepileptic medications can be given to treat seizures. Surgery can also be performed to remove tumors from the skin, brain, and so forth.

Researchers are exploring novel ways to treat tuberous sclerosis. According to the National Institute of Neurological Disorders and Stroke:

“Research studies run the gamut from very basic scientific investigation to clinical translational research. For example, some investigators are trying to identify all the protein components that are in the same 'signaling pathway' in which the TSC1 and TSC2 protein products and the mTOR protein are involved. Other studies are focused on understanding in detail how the disease develops, both in animal models and in patients, to better define new ways of controlling or preventing the development of the disease. Finally, clinical trials of rapamycin are underway (with NINDS and NCI support) to rigorously test the potential benefit of this compound for some of the tumors that are problematic in TSC patients.”

Parting Thoughts

If you or a loved one is diagnosed with tuberous sclerosis, please know that the prognosis or long-term outlook for this condition is highly variable. Although some infants with this condition face lifelong seizures and severe mental retardation, others go on to live otherwise healthy lives. Prognosis ultimately depends on the extent of tumor dissemination or spread. Nevertheless, people with this condition should be closely monitored for complications because there is always the threat that a brain or kidney tumor could become serious and life-threatening.


Darling TN. Chapter 140. Tuberous Sclerosis Complex. In: Goldsmith LA, Katz SI, Gilchrest BA, Paller AS, Leffell DJ, Wolff K. eds. Fitzpatrick's Dermatology in General Medicine, 8e. New York, NY: McGraw-Hill; 2012.

Kemp WL, Burns DK, Brown TG. Chapter 6. Genetic Disorders. In: Kemp WL, Burns DK, Brown TG. eds. Pathology: The Big Picture. New York, NY.

Tuberous Sclerosis Fact Sheet. National Institute of Neurological Disorders and Stroke.

Zhou J, Pollak MR. Polycystic Kidney Disease and Other Inherited Disorders of Tubule Growth and Development. In: Kasper D, Fauci A, Hauser S, Longo D, Jameson J, Loscalzo J. eds. Harrison's Principles of Internal Medicine, 19e. New York, NY: McGraw-Hill; 2015.

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