Tuberous Sclerosis

What is Tuberous Sclerosis?

Tuberous sclerosis complex (TSC) is a genetic condition passed down through families. It’s characterized by a higher likelihood of forming hamartomas, which are benign, or non-cancerous, tumors. This condition happens due to flaws in two specific genes, TSC1 and TSC2, and it’s known to cause neurological problems, such as epilepsy and intellectual disability. Other body systems that can be affected include the lungs, kidneys, skin, and heart. TSC is normally diagnosed in childhood or infancy when children may show signs of delayed development, skin changes, or seizures. However, it can be diagnosed earlier or later based on various symptoms.

Some symptoms, like heart muscle tumors or cortical tubers, which are abnormal cell growths in the brain, may be present before birth. Other signs, like kidney and lung lesions, are usually diagnosed in adulthood. The signs of the disease can vary based on the person’s stage of development. Skin lesions are found in 90% of patients of all ages, while light-colored spots are usually found in early childhood. Nail fibromas, which are small, benign skin tumors, appear around puberty, and facial angiomas, which are clusters of blood vessels on the face, are more common during the teenage years. The course of this disease can vary a lot. The outcome may be unpredictable, and follow-up care involves a thorough evaluation, often at specialized medical centers. This disorder can be overwhelming for some patients and their families, making education and counseling really important.

What Causes Tuberous Sclerosis?

Tuberous sclerosis is a complex condition which is caused by mutations or changes in two specific genes, known as TSC1 and TSC2. TSC1 is located on chromosome 9 and is connected to the production of a protein called hamartin. On the other hand, TSC2 is found on chromosome 16 and is related to the production of a protein known as tuberin. Mutations in these genes can lead to the formation of the characteristic tumors found in tuberous sclerosis. It’s important to note that these gene mutations can either be inherited from a parent or occur spontaneously.

Around 15% of those diagnosed with tuberous sclerosis do not show any identifiable genetic mutations. In the majority of cases, there is no known family history of the illness. However, if one parent has tuberous sclerosis, there is a 50% risk that their children will inherit the disease. Both men and women are equally affected.

The proteins produced by the TSC1 and TSC2 genes, hamartin and tuberin, help control cell growth and division in the body, and also play a role in preventing tumor growth.

Mutations in these genes can also affect the development of the central nervous system. They can deactivate a protein complex that regulates cell growth and metabolism. If this complex is not working correctly, it can lead to uncontrolled cell growth and the formation of solid tumors.

This process can also impact the brain and skin, affecting brain structure, nerve cell migration, and the formation of nerve cells. These irregularities can cause epilepsy and cognitive issues seen in tuberous sclerosis. It can also result in lighter skin patches.

Tuberous sclerosis has also been linked to a protein called vascular epithelial growth factor D (VEGF-D), most notably in conditions like lymphangioleiomyomatosis and kidney tumors known as angiomyolipomas. Levels of this protein have been noted to decrease when the cell growth regulation is restored. Currently, measuring VEGF-D levels is not a common practice outside of research settings.

Risk Factors and Frequency for Tuberous Sclerosis

Tuberous sclerosis complex is a condition that affects around 1 in 6,000 to 1 in 10,000 newborns, making its overall occurrence approximately 1 in 20,000 people. This condition can be quite unpredictable, usually affecting various organs and occurring among all racial groups. It’s interesting to note that in a study involving 125 patients, the average age when symptoms first showed up was 7 months. Furthermore, women with Tuberous sclerosis complex will typically be diagnosed with an additional lung condition, known as pulmonary lymphangioleiomyomatosis, around the age of 35.

Signs and Symptoms of Tuberous Sclerosis

Tuberous Sclerosis Complex (TSC) often differs greatly from patient to patient, and symptoms can continue to develop throughout a person’s life. Various brain abnormalities are common, with seizures affecting up to 90% of patients with TSC, usually appearing before the age of 3. A type of brain tumor called Subependymal giant cell astrocytoma is seen in up to 20% of patients, generally appearing in the first 20 years of life. These tumors can be dangerous, leading to other brain conditions and even death. Mental health issues are seen in approximately 90% of TSC patients, including learning disabilities, behavioral challenges, ADHD, OCD, and conditions on the autism spectrum. In fact, about 50% of TSC patients show signs of autism. There is some evidence that these symptoms can improve with certain medications.

Signs of TSC also often appear on the skin and are quite common. These skin symptoms are a major part of diagnosing TSC. Common skin conditions include facial angiofibromas, which affect 75% of patients; hypomelanotic macules, light-colored skin patches seen in about 90% of patients; fibrous plaques on the face or scalp; and Shagreen patches, thick, leathery skin lesions. In addition, small tumors can develop around the fingernails and toenails, especially after injury, most commonly on the toes.

• Seizures (before the age of 3)
• Subependymal giant cell astrocytoma (in the first 20 years of life)
• Mental health issues
• Facial angiofibromas
• Hypomelanotic macules
• Fibrous plaques on the face or scalp
• Shagreen patches
• Small tumors around the fingernails and toenails

Another condition associated with TSC called Lymphangioleiomyomatosis (LAM) mainly affects women of childbearing age. In patients with TSC, anywhere from 30% to 80% have evidence of LAM on medical imaging scans. LAM usually doesn’t cause symptoms, but when they do appear, they may include chest pain or sudden trouble breathing that could indicate a spontaneous pneumothorax, a condition where air leaks into the space around the lungs.

Cardiac lesions can affect 50% to 70% of patients with TSC, potentially causing death in newborns but frequently disappearing by early childhood. A study involving 125 patients revealed that these heart muscle tumors were the second most common symptom of TSC in young children and infants after seizures. Another common issue is renal angiomyolipoma. These are benign kidney tumors that appear in 55% to 75% of patients, usually showing no symptoms, but can sometimes cause pain in the side, blood in the urine, or a tender abdominal mass.

Tuberous sclerosis can usually be diagnosed during childhood when distinctive skin features start to appear. Diagnosis considers both major and minor clinical symptoms of the condition.

Testing for Tuberous Sclerosis

Tuberous sclerosis is typically diagnosed based on a patient’s symptoms, but genetic testing can also be used to confirm the diagnosis. Genetic testing is not always necessary if a patient clearly shows symptoms of the disease. However, it can provide helpful information for other family members. Testing for specific genes, TSC1 and TSC2, can find mutations in 75% to 95% of cases. These mutations cause the TSC1 or TSC2 proteins to stop working, which ultimately leads to the disease.

According to guidelines from the International Tuberous Sclerosis Complex Conference in 2012, the diagnosis of tuberous sclerosis depends on certain major and minor features.

Major Features include:

* White patches on the skin (more than two patches that are at least 5 mm in size)
* Skin growths known as angiofibromas (more than two) or a fibrous growth on the head
* Nail growths called ungual fibromas (more than one)
* A rough skin patch called a shagreen patch
* Multiple abnormal retinal growths in the eye
* Malformed areas in the brain cortex
* Small growths in the lining of the brain ventricles (subependymal nodules)
* A specific type of brain tumor (subependymal giant cell astrocytoma)
* A type of heart tumor (cardiac rhabdomyoma)
* A lung condition called lymphangioleiomyomatosis
* Kidney tumors called angiomyolipomas (more than one)

Minor Features include:

* Small white skin spots known as confetti skin lesions
* More than three dental enamel pits
* More than one fibroma inside the mouth
* A certain type of eye lesion (retinal achromic patch)
* Multiple kidney cysts
* Other non-kidney growths known as hamartomas

To confirm a tuberous sclerosis diagnosis, a patient must have either two major features or one major feature along with two minor features. If someone has either one major feature or at least two minor ones, a “possible diagnosis” is suggested. This diagnosis can be confirmed through genetic testing or observing the clinical symptoms.

Given that the majority of patients with tuberous sclerosis present skin abnormalities, a detailed skin examination should be conducted, often with a Wood’s lamp to identify lighter skin patches. Furthermore, an in-depth eye examination is important to identify possible eye growths.

Imaging tests, such as echocardiography (a type of ultrasound), magnetic resonance imaging (MRI), or CT scans can also help identify signs of the disease like heart and brain tumors or kidney angiomyolipomas (benign fatty tumors). CT or MRI scans are typically needed to exclude the possibility of cancer and to get a clearer understanding of the disease.

Treatment Options for Tuberous Sclerosis

People with a medical condition called tuberous sclerosis (TSC) are advised to undergo lifelong monitoring to watch for common symptoms. This applies particularly to children, who should have check-ups once every one to three years, including scans to examine their interna functions. As TSC tends to affect various body systems, these check-ups should be thorough. Dermatological (skin) checks can also help spot skin growths, known as angiofibromas, early. These growths may cause changes in appearance that might need treatment with laser therapy or surgery. Skin symptoms often react well to a group of drugs known as mTOR inhibitors, which prevent certain cell activities.

For TSC-related epilepsy, anticonvulsants, which help control seizures, are frequently needed. A third of patients experience seizures that can’t be controlled with drugs, and in such cases, surgery may be necessary. Urgent brain surgery may also be needed for severe complications like excessive fluid buildup in the brain, called hydrocephalus. A type of brain tumor called subependymal giant cell astrocytomas (SEGA), which causes symptoms mostly due to obstructive hydrocephalus, is typically treated with surgery. However, this surgery poses a higher risk of death and complications, such as partial paralysis, bleeding, infection, and mental decline. Asymptomatic SEGA, which doesn’t show any symptoms, is usually treated with mTOR inhibitors.

TSC patients commonly develop noncancerous kidney tumors called angiomyolipomas, which may need to be blocked using a procedure called arterial embolization if they’re larger than 3.5 cm. This procedure aims to prevent the need for complete kidney removal and lower kidney complications. Still, complications, including chronic kidney disease, remain common despite these efforts. If these tumors cause bleeding, the best treatment is arterial embolization followed by medicines called corticosteroids. After embolization, the tumors often recur, so mTOR inhibitors are the primary treatment.

Half to three-quarters of TSC patients develop renal (kidney) angiomyolipomas, and treatment is required for tumors larger than 6 cm, symptoms, pregnancy, or other high-risk situations. Both sirolimus and everolimus, types of an mTOR inhibitor, are used to treat renal angiomyolipomas and are preferred over surgery. These medications are generally used intermittently to prevent the regrowth of the tumor. mTOR inhibitors are also thought to reduce cyst size and number in associated kidney diseases.

Lymphangiomyomatosis (LAM), a lung disease, can also be treated with mTOR inhibitors. Females should be screened for LAM starting at age 18 and then every 5 to 7 years until menopause or if they develop respiratory symptoms. For patients with LAM, they might need to have an annual lung function test. Chylothorax, a condition where lymphatic fluid accumulates in the space between the lung and chest wall, happens in about 7% to 10% of patients with LAM. It has been traditionally treated with a fat-free or low-fat diet, which can be restrictive and put patients at risk for malnutrition. Surgical techniques to manage this condition have been used, but recent studies suggest the use of a mTOR inhibitor, sirolimus, could effectively control this rare complication.

What else can Tuberous Sclerosis be?

When trying to figure out the underlying medical condition in a patient, doctors may consider a variety of possible illnesses based on symptoms shown. In some cases, these could include:

• Tuberous sclerosis complex (TSC) and neurofibromatosis type 1 (NF1), both of which are genetically inherited disorders that affect the nervous system and skin. However, NF1 usually doesn’t involve issues with cognitive function or seizures — common problems associated with TSC. The negative impacts of NF1 are mainly due to tumors in the central nervous system and nerve coverings. NF1 can be recognized by the presence of several “cafe-au-lait” (coffee with milk) spots on the skin and might also come with bone abnormalities.
• Other conditions that affect both the nervous system and skin and might show similar symptoms are neurofibromatosis type 2, ataxia-telangiectasia, von Hippel Lindau syndrome, and Sturge-Weber syndrome.
• Birt-Hogg-Dubé syndrome and multiple endocrine neoplasia type 1 (MEN1) may be considered if the patient presents with red growths on their face known as angiofibromas. However, these conditions typically develop these symptoms later in life compared to TSC.

Please refer to related medical resources for a more in-depth understanding.

What to expect with Tuberous Sclerosis

Tuberosclerosis Complex (TSC) affects patients differently. This means that each person will exhibit different symptoms and their treatment plans will also vary. It’s important to know that TSC significantly affects the quality of life for patients and their caregivers. Compared to those without TSC, individuals with this condition also face a higher risk of mortality, with a recorded death rate between 4.8% and 8.3% over a follow-up period of 8 to 17.4 years.

Deaths related to TSC are usually due to complications from seizures or kidney growths called Renal Angiomyolipomas. Other causes of death include lung infection, complications from Lymphangioleiomyomatosis (LAM, a rare lung disease), and newborn heart failure related to heart tumors known as Rhabdomyomas.

Lastly, it’s worth mentioning that TSC patients who receive lung transplants due to LAM have a survival rate of about 65% after 5 years.

Possible Complications When Diagnosed with Tuberous Sclerosis

Tuberous sclerosis is a medical condition that affects multiple body systems and often presents in different tissues across a person’s life. Kidney issues are quite common in people with tuberous sclerosis, including conditions like renal angiomyolipomas, polycystic kidney disease, renal cysts, and kidney cancer (renal cell carcinomas). The risk for kidney cancer is similar to that of the overall population, but it typically shows up at a younger age in patients with tuberous sclerosis.

In addition, up to 56% of patients with lymphangioleiomyomatosis (LAM), a lung disease, may develop a collapsed lung or pneumothorax. If this happens, it is highly likely it will occur again, typically around 4.4 times. Therefore, a procedure called pleurodesis is often recommended to decrease the likelihood of another pneumothorax, although recurrence rates are still between 18% and 32%. A new surgical technique, total pleural covering (wrapping the visceral pleura with an oxidized regenerated cellulose mesh) seems to be showing promising outcomes.

It’s also important to note that traveling by air, which leads to changes in air pressure, can raise the risk of pneumothorax for patients with LAM. One study found the rate of occurrence at 1.1% per flight. Other potential conditions include seizures, which are common in tuberous sclerosis and often resistant to common medical treatments; therefore, surgery might be necessary.

While mTOR inhibitors have significantly improved the prognosis and lowered the associated health risks and death rates of Tuberous Sclerosis, these drugs can have side effects. These include stomatitis (inflammation of the mouth and lips), increased risk for infections, and menstrual irregularities. More severe side effects can usually be managed with temporary stopping or lowering the drug dosage.

Side Effects

• Stomatitis (inflammation of the mouth and lips)
• Increased risk for infections
• Menstrual irregularities
• Pneumonia
• Severe side effects in children
• Skin rash
• High levels of lipids
• High blood sugar levels
• Low blood cell counts
• Proteinuria (presence of excess proteins in the urine)

Preventing Tuberous Sclerosis

Tuberous sclerosis is a medical condition that can vary greatly from person to person, with numerous potential symptoms. The complexity and uncertainty of this illness can be overwhelming, especially for family members. Genetic counseling is beneficial for patients and parents of children with tuberous sclerosis complex. If parents have this condition, they need to know there is about a 50% chance their child may also have it. If parents don’t have the disease, the likelihood of having another child with tuberous sclerosis drops to between 1% and 2%. Parents can also be tested, as it’s not uncommon for them to show signs of the disease after their children.

Another issue to note is that exposure to estrogen, either through birth control pills or pregnancy, can enhance the symptoms of a related condition called lymphangioleiomyomatosis (LAM), which is common in people with tuberous sclerosis. Therefore, women should be aware of this risk before planning a pregnancy or starting birth control that contains estrogen. Moreover, patients with LAM can experience a spontaneous lung collapse, particularly if they have a history of this occurrence or if they often travel by air. Therefore, they should be educated about these risks and receive appropriate vaccinations to protect against upper respiratory infections. Lastly, they should be advised to regularly use sunscreen, as this can help protect any skin lesions that have less pigmentation.