Overview Of Tuberous Sclerosis Complex
Tuberous sclerosis complex is a genetic disorder characterized by the growth of numerous noncancerous (benign) tumors in many parts of the body. These tumors can occur in the skin, brain, kidneys, and other organs, in some cases leading to significant health problems. Tuberous sclerosis complex also causes developmental problems, and the signs and symptoms of the condition vary from person to person.
Virtually all affected people have skin abnormalities, including patches of unusually light-colored skin, areas of raised and thickened skin, and growths under the nails. Tumors on the face called facial angiofibromas are also common beginning in childhood.
Tuberous sclerosis complex often affects the brain, resulting in a pattern of behaviors called TSC-associated neuropsychiatric disorders (TAND). These disorders include hyperactivity, aggression, psychiatric conditions, intellectual disability, and problems with communication and social interaction (autism spectrum disorder). Some individuals with tuberous sclerosis complex have seizures or benign brain tumors that can cause serious or life-threatening complications.
Kidney tumors are common in people with tuberous sclerosis complex; these growths can cause severe problems with kidney function and may be life-threatening in some cases. Additionally, tumors can develop in the heart and the light-sensitive tissue at the back of the eye (the retina). Some women with tuberous sclerosis complex develop lymphangioleiomyomatosis (LAM), which is a lung disease characterized by the abnormal overgrowth of smooth muscle-like tissue in the lungs that cause coughing, shortness of breath, chest pain, and lung collapse.
Commonly Associated With
Bourneville disease, Bourneville phakomatosis, cerebral sclerosis, epiloia, sclerosis tuberosa, tuberose sclerosis
Causes Of Tuberous Sclerosis Complex
Tuberous sclerosis is an inherited condition. Changes (mutations) in one of two genes, TSC1 and TSC2, are responsible for most cases.
Only one parent needs to pass on the mutation for the child to get the disease. However, two-thirds of cases are due to new mutations. In most cases, there is no family history of tuberous sclerosis.
This condition is one of a group of diseases called neurocutaneous syndromes. Both the skin and central nervous system (brain and spinal cord) are involved.
There are no known risk factors, other than having a parent with tuberous sclerosis. In that case, each child has a 50% chance of inheriting the disease.
Mutations in the TSC1 or TSC2 gene can cause tuberous sclerosis complex. The TSC1 and TSC2 genes provide instructions for making the proteins hamartin and tuberin, respectively. Within cells, these two proteins likely work together to help regulate cell growth and size. The proteins act as tumor suppressors, which normally prevent cells from growing and dividing too fast or in an uncontrolled way.
People with tuberous sclerosis complex are born with one mutated copy of the TSC1 or TSC2 gene in each cell. This mutation prevents the cell from making functional hamartin or tuberin from the altered copy of the gene. However, enough protein is usually produced from the other, normal copy of the gene to regulate cell growth effectively. For some types of tumors to develop, a second mutation involving the other copy of the TSC1 or TSC2 gene must occur in certain cells during a person’s lifetime.
When both copies of the TSC1 gene are mutated in a particular cell, that cell cannot produce any functional hamartin; cells with two altered copies of the TSC2 gene are unable to produce any functional tuberin. The loss of these proteins allows the cell to grow and divide in an uncontrolled way to form a tumor. In people with tuberous sclerosis complex, a second TSC1 or TSC2 mutation typically occurs in multiple cells over an affected person’s lifetime. The loss of hamartin or tuberin in different types of cells leads to the growth of tumors in many different organs and tissues.
Symptoms Of Tuberous Sclerosis Complex
Skin symptoms include:
- Areas of the skin that are white (due to decreased pigment) and have either an ash leaf or confetti appearance
- Red patches on the face containing many blood vessels (facial angiofibromas)
- Raised patches of skin with an orange-peel texture (shagreen spots), often on the back
Brain symptoms include:
- Autism spectrum disorders
- Developmental delays
- Intellectual disability
Other symptoms include:
- Pitted tooth enamel.
- Rough growths under or around the fingernails and toenails.
- Rubbery noncancerous tumors on or around the tongue.
- Lung disease known as LAM (lymphangioleiomyomatosis). This is more common in women. In many cases, there are no symptoms. In other people, this can lead to shortness of breath, coughing blood, and lung collapse.
- The symptoms vary from person to person. Some people have normal intelligence and no seizures. Others have intellectual disabilities or difficult-to-control seizures.
Exams & Tests
Signs may include:
- Abnormal heart rhythm (arrhythmia)
- Calcium deposits in the brain
- Noncancerous “tubers” in the brain
- Rubbery growths on the tongue or gums
- Tumor-like growth (hamartoma) on the retina, pale patches in the eye
- Tumors of the brain or kidneys
Tests may include:
- CT scan of the head
- Chest CT
- Echocardiogram (ultrasound of the heart)
- MRI of the head
- Ultrasound of the kidney
- Ultraviolet light examination of the skin
- DNA testing for the two genes that can cause this disease (TSC1 or TSC2) is available.
Regular ultrasound checks of the kidneys are important to make sure there is no tumor growth.
Treatment Of Tuberous Sclerosis Complex
There is no known cure for tuberous sclerosis. Because the disease can differ from person to person, treatment is based on the symptoms.
Depending on the severity of the intellectual disability, the child may need special education.
Some seizures are controlled with medicine (vigabatrin). Other children may need surgery.
Small growths on the face (facial angiofibromas) may be removed by laser treatment. These growths tend to come back, and repeat treatments will be needed.
Cardiac rhabdomyomas commonly disappear after puberty. Surgery to remove them is usually not needed.
Brain tumors can be treated with medicines called mTOR inhibitors (sirolimus, everolimus).
Kidney tumors are treated with surgery, or by reducing the blood supply using special x-ray techniques. mTOR inhibitors are being studied as another treatment for kidney tumors.
Tuberous sclerosis complex affects about 1 in 6,000 people. Tuberous sclerosis complex has an autosomal dominant pattern of inheritance, which means one copy of the altered gene in each cell is sufficient to increase the risk of developing tumors and other problems with development. In about one-third of cases, an affected person inherits an altered TSC1 or TSC2 gene from a parent who has the disorder. The remaining two-thirds of people with tuberous sclerosis complex are born with new mutations in the TSC1 or TSC2 gene. These cases, which are described as sporadic, occur in people with no history of tuberous sclerosis complex in their family. TSC1 mutations appear to be more common in familial cases of tuberous sclerosis complex, while mutations in the TSC2 gene occur more frequently in sporadic cases.
Rarely, individuals with tuberous sclerosis complex do not have an identified mutation in the TSC1 or TSC2 gene. Research suggests that in these cases the condition may be caused by a random mutation in the TSC1 or TSC2 gene that occurs very early in development. As a result, some of the body’s cells have a normal version of the gene, while others have the mutated version. This situation is called mosaicism.