The ABC’s of TSC (Tuberous Sclerosis Complex)
What is 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?
TSC affects about 50,000 people in the US and one million worldwide, with an estimated incidence of 1 in 6,000 live births. It plays no favorites -- it affects both men and women 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 in a family.
The most common symptoms of TSC are seizures and developmental delay as well as 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 condition may become apparent any time from infancy to adulthood but usually occurs between 2 and 6 years of age.
The Brain: A Major Target
In 95% of individuals with 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 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), and social or emotional withdrawal.
Skin lesions, including those found on the face, body and nails, are found in almost all individuals with 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.
Everolimus (Afinitor, Zortress) may also be used to treat brain or kidney tumors that cannot be surgically removed.
Tumors and cysts of the kidney are common among people who have tuberous sclerosis complex. 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.
Cardiac (heart) involvement is common in 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. Afinitor (everolimus) is approved to treat these heart lesions called subependymal giant cell astrocytomas (SEGAs).
An estimated three-quarters of people with tuberous sclerosis 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.
Lung tumors and cysts call lymphangioleiomyomatosis develop in about one-third of adult women with TSC. In most cases, these cysts and tumors do not cause a problem.
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.
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
Advancements in research with medicines like mTOR inhibitors shows great promise in developing new and improved treatment options. mTOR inhibitors work by blocking the chemical reaction that causes tumors to grow.
- Rapamune (generic name: sirolimus)
- Afinitor (generic name: everolimus)
- Afinitor Disperz Tablets for oral suspension
are examples of mTOR inhibitors that have been shown to shrink certain tumors in the kidneys (AMLs), brain (SEGAs), lungs and certain skin lesions on the face (facial angiofibromas).
mTOR inhibitors are also being tested to see if they can help with epilepsy, autism, and thinking and learning problems.
What is the Outlook of Patients With TSC?
Although there's no cure for tuberous sclerosis, many people live a full lifespan. However, 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. Children with severe mental disability or uncontrollable seizures usually do poorly.
The tumors in this disease tend to be noncancerous (benign). However, some tumors, particularly kidney or brain tumors, can rarely become cancerous.
New mTOR inhibitor treatments are paving the way for treatments on the skin, kidney and brain that can have an impact on outcomes.
Finished: The ABC’s of TSC (Tuberous Sclerosis Complex)
- 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 July 31, 2017 at http://www.ncbi.nlm.nih.gov/pubmed/27222056.
- 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 July 31, 2017 at http://www.ncbi.nlm.nih.gov/pubmed/24810875.
- Massachusetts General Hospital. Living with TSC. Accessed July 31, 2017 at http://www.massgeneral.org/tsc/
- 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 July 31, 2017 at http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4748639/