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The ABC’s of TSC (Tuberous Sclerosis Complex)

Medically reviewed by Leigh Ann Anderson, PharmD. Last updated on April 12, 2021.

What is Tuberous Sclerosis Complex (TSC)?

Tuberous Sclerosis Complex (TSC for short, or often referred to as tuberous sclerosis or TS) is a rare genetic condition that affects many organs and can cause noncancerous (benign) tumors in the skin, kidney, brain, heart, eyes, lungs and other organs.

The severity of TSC can range from mild, such as skin abnormalities, to severe with seizures, learning disabilities or renal failure.

TSC is a genetic disorder caused by a mutation in one of two genes: TSC1 or TSC2. These genes suppress abnormal cell growth in the body by inhibition of a protein called mammalian target of rapamycin, or "mTOR" for short.

When either the TSC1 or TSC2 gene is defective, cell growth is not adequately suppressed and tuberous sclerosis complex results, leading to abnormal lesion growth.

Who Gets TSC?

Tuberous Sclerosis Complex (TSC) affects about 50,000 people in the US and one million worldwide, with an estimated incidence of 1 in 6,000 live births. The condition may become apparent any time from infancy to adulthood but usually occurs between 2 and 6 years of age.

It plays no favorites -- it affects both sexes and all races. In general, one third of individuals with TSC inherit the genetic condition from a parent. Two thirds of all cases are sporadic, or occur for the first time within a family.

The most common symptoms of TSC are:

  • seizures
  • developmental delay
  • benign tumors and lesions which can affect virtually every organ system of the body including the brain, kidneys, heart, lungs, eyes, skin, and other organs.

The Brain: A Major Target

In 95% of individuals with Tuberous Sclerosis Complex (TSC), the brain is affected by some form of tumor growth. These tumors affect the way the brain functions and leads to other complications.

Epilepsy (seizure) is the most common medical condition in TSC, occurring in 80 to 90 percent of individuals. In about one third of individuals, seizures starts out as infantile spasms, which are repetitive spasms of the head and legs.

Individuals with TSC also have an increased risk of neurologic and behavioral impairment. Although about half of individuals with TSC have normal intelligence, developmental delay and learning disabilities are commonly found in children with TSC.

Additionally, up to 60% of individuals with TSC can develop autism. Behavioral problems can include:

  • hyperactivity
  • rage
  • aggression
  • repeated behaviors (tics)
  • social or emotional withdrawal.

The Skin

Skin lesions, including those found on the face, body and nails, are found in almost all individuals with Tuberous Sclerosis Complex (TSC). The earliest sign may be white or light-colored skin patches which are best seen under ultraviolet light. As a child grows older, a characteristic facial rash that often resembles acne (facial angiofibromas) may develop across the nose and cheeks.

Specially formulated topical mTOR inhibitor ointments can be compounded and prescribed. Sirolimus or everolimus ointment have been prescribed to treat the acne lesions that occur in patients with TSC.

Everolimus (Afinitor) may also be used to treat brain or kidney tumors that cannot be surgically removed.

Clinical study: Topical Sirolimus Ointment for Cutaneous Angiofibromas in Subjects With Tuberous Sclerosis Complex

The Kidneys

Tumors and cysts of the kidney are common among people who have Tuberous Sclerosis Complex (TSC). Cysts are usually small in size and number and cause few problems; however, a small number of patients will develop symptoms similar to polycystic kidney disease.

Benign kidney tumors called angiomyolipomas (AML’s) are made up of vascular tissue, smooth muscle, and fat. They usually grow very slowly and may not be problematic until young adulthood.

  • Afinitor (everolimus) is used to treat angiomyolipomas.

Larger kidney lesions can cause bleeding and pain and may require surgical intervention.

The Heart

Cardiac (heart) involvement is common in Tuberous Sclerosis Complex (TSC) and is found in up to two thirds of individuals. Lesions in the heart can block blood flow or cause abnormal heart rhythms.

Benign heart tumors (cardiac rhabdomyomas) are often an early sign of TSC. Fortunately these tumors often regress spontaneously, shrinking or completely disappearing with time. They are largest at birth and usually shrink as the child gets older.

However, if lesions interfere with the function of the heart, they may need to be removed.

The Eyes

An estimated three-quarters of people with Tuberous Sclerosis Complex (TSC) will develop one or more tumors inside the eyes.

These tumors, which are benign and called retinal hamartoma, occur on the surface of the retina, the inside layer of the eye responsible for receiving outside visual signals that go to the brain.

Lesions may appear as white patches on light-sensitive tissue on the retina, but rarely grow big enough to affect vision. However, these lesions can be see upon eye exam with an ophthalmologist and often are the first clinical sign of TSC noted.

The Lungs

Lung tumors and cysts called lymphangioleiomyomatosis develop in about one-third of adult women with Tuberous Sclerosis Complex (TSC). In most cases, these cysts and tumors do not cause serious problems.

However, a small number of women will experience asthma–like symptoms including shortness of breath. In serious cases progressive lung failure may develop. It is unclear why women are predominantly affected.

Rapamune (sirolimus) is approved to treat lymphangioleiomyomatosis. Therapeutic drug monitoring and blood testing will be required to maintain the correct blood concentrations.

How is TSC Diagnosed?

Diagnosis is usually based on imaging of the brain, kidneys and heart using:

The skin is examined often with the aid of ultraviolet light especially on babies or children with light skin. There is no single clinical feature absolutely specific to TSC.

DNA testing for either of the two genes that can cause this disease (TSC1 or TSC2) has become available, and a geneticist, as well as other specialists may be involved in the care of patients with TSC.

Treatments for TSC

There is no cure for TSC but several agents are available for symptom treatment.

Afinitor is approved to shrink certain tumors in the kidneys (AMLs), and Afinitor Disperz is cleared for treatment of brain tumors (subependymal giant cell astrocytoma or SEGAs) that requires treatment but cannot be surgically removed.

Advancements in research with medicines like mTOR inhibitors show great promise in developing new and improved treatment options. mTOR inhibitors work by blocking the chemical reaction that causes tumors to grow. mTOR inhibitors approved by the FDA include:

Afinitor is approved to shrink certain tumors in the kidneys (AMLs) in aptients not requiring immediate surgery, and Afinitor Disperz is cleared for treatment of brain tumors (subependymal giant cell astrocytoma or SEGAs) that requires treatment but cannot be surgically removed. In April 2018, the FDA also approved Afinitor Disperz for the adjunctive treatment of adults and children 2 years and older with TSC-associated partial-onset seizures.

Rapamune (sirolimus) is an oral treatment approved for (lymphangioleiomyomatosis or LAM) in TSC. LAM is an abnormal growth of smooth muscle cells and cysts in the lungs that can lead to shortness of breath, chest pain, cough and fluid around the lungs. LAM occurs most frequently in women. Rapamune can also be used to shrink large angiomyolipomas of the kidney, but is not specifically FDA approved for this use.

Sabril (vigabatrin), an oral GABA analogue antiseizure medicine, is also used to treat infantile spasms in TSC, although it has significant vision loss side effects. Sabril is not used as a first line agent.

In August 2020, Epidiolex (cannabidiol) was approved by the FDA to treat TSC-associated seizures in patients 1 year of age and older.

What is the Outlook of Patients With TSC?

Although there's no cure for Tuberous Sclerosis Complex (TSC), many people live a full lifespan. The tumors in this disease tend to be noncancerous (benign). However, some tumors, particularly kidney or brain tumors, can rarely become cancerous.

  • The prognosis of individuals with TSC varies from individual to individual.
  • The severity of the complications determines the long term outlook, and symptoms can range from mild to extremely severe.
  • Most individuals who are mildly affected with TSC and receive care can expect an active and productive life with normal life expectancy. However, children with severe mental disability or uncontrollable seizures usually do poorly.

New mTOR inhibitor treatments are paving the way for treatments on the skin, kidney and brain that can have a positive impact on outcomes.

Finished: The ABC’s of TSC (Tuberous Sclerosis Complex)

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Sources

  • Tuberous Sclerosis Fact Sheet. National Institute of Neurological Disorders and Stroke. National Institutes of Health (NIH). Accessed April 12, 2021 at https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Tuberous-Sclerosis-Fact-Sheet#3220_6
  • Topical Sirolimus Ointment for Cutaneous Angiofibromas in Subjects With Tuberous Sclerosis Complex. Clinical Trials.gov. ClinicalTrials.gov Identifier: NCT03363763. Accessed April 12, 2021 at https://clinicaltrials.gov/ct2/show/NCT03363763
  • Jóźwiak S, Sadowski K, Kotulska K, Schwartz RA. Topical Use of Mammalian Target of Rapamycin (mTOR) Inhibitors in Tuberous Sclerosis Complex - A Comprehensive Review of the Literature. Pediatr Neurol. 2016:30380-5. Accessed April 7, 2020
  • Dill PE, De Bernardis G, Weber P, Lösch U. Topical everolimus for facial angiofibromas in the tuberous sclerosis complex. A first case report. Pediatr Neurol. 2014 Jul;51(1):109-13. Accessed April 7, 2020
  • Tahiri Elousrouti L, Lamchahab M, Bougtoub N, et al. Subependymal giant cell astrocytoma (SEGA): a case report and review of the literature. J Med Case Rep. 2016 Feb 9;10:35. doi: 10.1186/s13256-016-0818-6. Accessed April 7, 2020.

Further information

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