At a glance......
- 1 Other Names for This Condition
- 2 Causes of Tuberous Sclerosis Complex
- 3 Is TSC inherited?
- 4 Symptoms of Tuberous Sclerosis Complex
- 5 Diagnosis of Tuberous Sclerosis Complex
- 6 Treatment of Tuberous Sclerosis Complex
- 7 What is the prognosis?
- 8 QUESTIONS
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Sclerosis tuberose is also known as Cerebral sclerosis, Bourneville Phakomatosis, Bourneville disease, Tuberous sclerosis, tuberous sclerosis complex is a neurocutaneous disorder (phakomatosis) characterized by the development of multiple benign tumors of the embryonic ectoderm (e.g. skin, eyes, and nervous system).
Tuberous sclerosis complex is a multisystemic, autosomal dominant neurocutaneous genetic disorder with complete penetrance, hamartomatous growths in multiple organ systems that can evolve with hamartomas in multiple organs, by causing the growth of benign tumors, so-called hamartomas. As brain, skin, kidneys, heart, liver, lungs, and less frequently retina, gingiva, bones, and gastrointestinal tract can be affected, TSC patients require coordinated care of many specialties.
Hamartomas – plural of hamartoma; benign overgrowths of a mature cell type normal to the site or organ. They may be congenital or acquired
Tuberous sclerosis (also called tuberous sclerosis complex, or TSC) is a rare, multi-system genetic disease that causes non-cancerous (benign) tumors to grow in the brain and on other vital organs such as the kidneys, heart, eyes, lungs, and skin. It usually affects the central nervous system and can result in a combination of symptoms including seizures, impaired intellectual development, autism, behavioral problems, skin abnormalities, and kidney disease.
The severity of symptoms varies widely. Symptoms range from mild—allowing people to live independent, productive lives—to more severe symptoms that can affect everyday life and even be life-threatening. Many people with TSC show evidence of the disorder in the first year of life. However, clinical features can be subtle initially, and many signs and symptoms take years to develop. As a result, TSC can be unrecognized or misdiagnosed for years.
The name tuberous sclerosis comes from the characteristic tuber or potato-like nodules in the brain, which calcify with age and becomes hard or sclerotic. TSC occurs in all races and ethnic groups, and in both genders.
Other Names for This Condition
- Bourneville disease
- Bourneville phakomatosis
- Cerebral sclerosis
- Sclerosis tuberosa
- Tuberose sclerosis
- Bourneville Pringle Syndrome
- phakomatosis TS
- tuberous sclerosis complex
Causes of Tuberous Sclerosis Complex
TSC is caused by defects, or mutations, on two genes—TSC1 and TSC2. Only one of the genes needs to be affected for TSC to be present. The TSC1 gene is on chromosome 9 and produces a protein called hamartin. The TSC2 gene is on chromosome 16 and produces the protein tuberin. Scientists believe these proteins act as growth suppressors by inhibiting the activation of a protein called mTOR. Loss of regulation of mTOR occurs in cells lacking either hamartin or tuberin, and this leads to abnormal differentiation and development, and to the generation of enlarged cells, as are seen in TSC brain lesions.
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.
Is TSC inherited?
Although some individuals inherit the disorder from a parent with TSC, most cases occur as sporadic cases due to new, spontaneous mutations in TSC1 or TSC2—meaning neither parent has the disorder or the faulty gene(s). Instead, a faulty gene first occurs in the affected individual.
In cases where TSC is inherited, only one parent needs to have the faulty gene in order to pass it on to a child (called autosomal dominant inheritance). If a parent has TSC, each child has a 50 percent chance of developing the disorder. Children who inherit TSC may not have the same symptoms as their parent and may have either a milder or a more severe form of the disorder.
In rare instances, people acquire TSC through a process called gonadal mosaicism. These individuals have parents with no apparent defects in the two genes that cause the disorder. Yet these parents can have a child with TSC because a portion of one of the parent’s reproductive cells (sperm or eggs) can contain the genetic mutation without the other cells of the body being involved. In cases of gonadal mosaicism, genetic testing of a blood sample might not reveal the potential for passing the disease to offspring.
Symptoms of Tuberous Sclerosis Complex
TSC can affect many different systems of the body, causing a variety of signs and symptoms that range from very mild to quite severe. Common symptoms include:
Benign tumors are most common in the brain, kidneys, heart, lungs, and skin. Cancerous tumors are rare in TSC and those that do occur primarily affect the kidneys.
Three types of brain lesions are seen in TSC:
- Cortical tubers – for which the disease is named, generally form on the surface of the brain but may also appear in the deep areas of the brain
- Subependymal nodules (SEN) – which form in the walls of the ventricles—the fluid-filled cavities of the brain, and
- Subependymal giant-cell astrocytomas (SEGA) – which develop from SEN and grow such that they may block the flow of fluid within the brain—causing a buildup of fluid and pressure that can lead to headaches and blurred vision.
Tumors called cardiac rhabdomyomas are often found in the hearts of infants and young children with TSC, and they are often seen on prenatal fetus ultrasound exams. If the tumors are large or there are multiple tumors, they can block circulation and cause death. However, if they do not cause problems at birth—when in most cases they are at their largest size—they usually become smaller with time and do not affect the individual in later life.
Benign tumors called pakoras are sometimes found in the eyes of individuals with TSC, appearing as white patches on the retina. Generally, they do not cause vision loss or other vision problems, but they can be used to help diagnose the disease.
Additional tumors and cysts may be found in other areas of the body, including the liver, lung, and pancreas. Bone cysts, rectal polyps, gum fibromas, and dental pits may also occur.
Seizures affect most individuals with TSC at some point during their life. While some kinds of seizures caused by TSC result in obvious convulsive movements, others alter awareness, behavior, or postural tone without convulsions. Seizures also can be difficult to control by medication, and sometimes surgery or other measures are used.
Cognitive disabilities affect some people with TSC. Developmental delay occurs in about one-half to two-thirds of people with TSC. Delays range from mild learning disabilities to severe impairment.
Behavior problems, including aggression, sudden rage, attention deficit hyperactivity disorder, acting out, obsessive-compulsive disorder, and repetitive, destructive, or self-harming behavior occur in children with TSC and can be difficult to manage. About one-third of children with TSC meet the criteria for autism spectrum disorder.
Tuberous sclerosis has a significant number of manifestations, involving many organ systems. The most common radiographic manifestations are:
- cortical or subependymal tubers and white matter abnormalities
- renal angiomyolipomas
- cardiac rhabdomyoma(s)
- cortical/subcortical tubers: 50% are in the frontal lobe; high T2 and low T1 with only 10% of tubers showing enhancement; frequently calcify after two years of age
- subependymal hamartomas
- 88% are associated with calcification, although calcification absent in early childhood
- visible within the first six months of age 4
- variable signal, frequently high T1 and iso to high T2
- enhancement is variable and is not a useful feature in distinguishing them from subependymal giant cell astrocytomas (SGCA); only serial growth is reliable 5,6
- subependymal giant cell astrocytomas (SGCA)
- peak occurrence 8-18 years
- tend to be large and demonstrate growth 5,6
- tend to have intense enhancement
- white matter abnormalities
- variable appearance, with nodular, ill-defined, cystic and band-like lesions seen
- radial bands are thought to be relatively specific for TS 7
- retinal phakomas
- rarer findings
- cerebellar atrophy
- infarcts (due to occlusive vascular disorders)
- cerebral aneurysms
- dysgenesis of the corpus callosum
- Chiari malformations
- arachnoid cysts
- renal angiomyolipoma(s)
- tuberous sclerosis accounts for 20% of all angiomyolipomas 3
- angiomyolipomas are seen in 55-75% of patient with tuberous sclerosis
- tend to be multiple, large and bilateral
- tend to grow and require surgical treatment, as the probability of hemorrhage is proportional to the size
- micro and macro aneurysms may be present 3
- fat may not be visible in up to 4.5% 1
- renal cysts: the TSC2 gene is located adjacent to the PCKD1 gene 3
- 18-53% of patients with tuberous sclerosis 1
- renal cell carcinoma and oncocytomas
- although rates of renal cell carcinoma are the same as in the general population, in patients with tuberous sclerosis, renal cell carcinoma tends to occur at a younger age 1
- retroperitoneal lymphangiomyomatosis (LAM)
- histologically identical to pulmonary LAM
- retroperitoneal cystic lesions
- chylous ascites, enlarged lymph nodes, dilatation of the thoracic duct
- gastrointestinal polyps
- pancreatic neuroendocrine tumors 12
- hepatic angiomyolipoma(s)
- lymphangioleiomyomatosis (LAM)
- rare (1%)
- some studies have described a lymphangiomyomatosis-like change to be present in 25-40% of female patients with tuberous sclerosis
- indistinguishable from sporadic LAM
- pneumothorax and chylous pleural effusions common
- ~80% 10-year survival
- multifocal micronodular pneumocyte hyperplasia (MMPH)
- characterized by multicentric well-demarcated nodular proliferation of type II pneumocytes
- benign, non-progressive
- differential diagnoses: miliary pulmonary opacities
- cardiac rhabdomyomas
- benign striated muscle tumor characterized by the presence of spider cells
- seen in 50-65% of patients with tuberous sclerosis
- 40-80% of patients with cardiac rhabdomyomas have tuberous sclerosis
- multiple or single
- typically involve the ventricular septum
- occur before the age of 1 year (75% of cases) 1
- typically regress before birth with spontaneous regression in 70% of children by age 4
- thoracic duct and aortic/pulmonary artery aneurysm
- myocardial fatty foci 14
- sclerotic bone lesions: 40-66% 1
- hyperostosis of the inner table of the calvaria
- periosteal new bone
- bone cysts 8
Cutaneous lesions are present in ~95% of cases, but are rarely appreciated radiographically 8:
- hypopigmented macules (ash leaf spots): seen in 90% of patients 1
- facial angiofibromas (Pringle nodules or adenoma sebaceum); seen in 75% of patients
- fibrous plaques of the forehead (15-20%)
- confetti lesions: variant of leukoderma spots
- shagreen patches: seen in 20-30% of patients
- periungual fibroma (Koenen tumors): 20% of patients
Skin abnormalities vary widely in individuals with TSC. Most cause no problems but are helpful in diagnosis. Some cases may cause disfigurement, necessitating treatment. The most common skin abnormalities include:
Hypomanic macules – (“ash leaf spots”), which are white or lighter patches of skin that may appear anywhere on the body and are caused by a lack of skin pigment or melanin—the substance that gives skin its color.
Facial angiofibromas (also called adenoma sebaceous) – are reddish spots or bumps which appear on the face (sometimes resembling acne) and consist of blood vessels and fibrous tissue.
Forehead plaques – are raised, discolored areas on the forehead which are common and unique to TSC and may help doctors diagnose the disorder.
Shagreen patches – are areas of thick leathery, pebbly skin, usually found on the lower back or nape of the neck.
Ungual or subungual fibromas – are small fleshy tumors that grow around and under the toenails or fingernails and may need to be surgically removed if they enlarge or cause bleeding. These usually appear later in life, ages 20-50.
Other skin features – that are not unique to individuals with TSC, including molluscum fibrosum or skin tags, which typically occur across the back of the neck and shoulders; café au lait spots or flat brown marks; and poliosis, a tuft or patch of white hair that may appear on the scalp or eyelids.
Kidney problems such as cysts and angiomyolipomas (benign growths of fatty tissue and muscle cells) occur in an estimated 70 to 80 percent of individuals with TSC. They usually occur between ages 15 and 30.
- Cysts are usually small, appear in limited numbers, and most often cause no serious problems. A very small percent of individuals with TSC develop large numbers of cysts during childhood, which may lead to bleeding, anemia, and kidney failure.
- Angiomyolipomas are the most common kidney lesions in TSC and can be found in people without TSC. Angiomyolipomas caused by TSC are usually found in both kidneys and in most cases do not produce symptoms. However, they can sometimes grow so large that they cause pain or kidney failure. Bleeding from angiomyolipomas may also occur, causing both pain and weakness. If severe bleeding does not stop naturally, there may be severe blood loss, resulting in profound anemia and a life-threatening drop in blood pressure, warranting urgent medical attention.
- Other rare kidney problems include renal cell carcinoma, developing from an angiomyolipoma, and oncocytomas, benign tumors unique to individuals with TSC.
Lung lesions are present in about one-third of adult women with TSC and are much less commonly seen in men. Lung lesions include lymphangioleiomyomatosis (LAM) and multinodular multifocal pneumocyte hyperplasia (MMPH). LAM is a tumor-like disorder in which cells proliferate in the lungs, and there is lung destruction with cyst formation. A range of symptoms can occur with LAM, with many TSC individuals having no symptoms, while others suffer with breathlessness, which can progress and be severe. MMPH is a more benign tumor that occurs in men and women equally.
As per the recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference, the diagnostic criteria for tuberous sclerosis include the following major and minor features[rx][rx]:
Hypomelanotic macules (more than 2, and at least 5-mm in diameter)
Angiofibromas (more than 2) or fibrous cephalic plaque
Ungual fibromas (more than 1)
Multiple retinal hamartomas
Subependymal giant cell astrocytoma
Angiomyolipomas (more than 1)
More than 2 angiofibromas, which are skin-colored growths of blood vessels in the skin or a thick (fibrous) patch of skin on the forehead
2 or more periungual fibromas or hard growths, around or under the fingernails or toenails
More than 3 light-colored areas on the skin, known as hypomelanotic macules or ash leaf spots
Shagreen patch, meaning a rough growth of tissue on the surface of the skin
Tubers, or thickened areas, found in the brain
Nodules (round growths) found in the brain
Subependymal giant cell astrocytoma (SEGA), a type of brain cancer
Cardiac rhabdomyoma, which is a benign, noncancerous heart growth
Angiomyolipoma of the kidney, which are benign growths that can cause serious medical problems; there is a low risk that these tumors could become cancerous
Lymphangiomyomatosis, which are multiple cysts or fluid-filled growths along the lymphatic system under the skin
Multiple hemangioblastomas, which are growths of newly formed blood vessels, of the brain, spinal cord, or eye
One or more hemangioblastomas in addition to kidney cysts, pancreatic cysts, pheochromocytoma, which is a rare growth in the cells of one of the adrenal glands, or kidney cancer
Confetti skin lesions
Dental enamel Pitts (more than 3)
Intraoral fibromas (more than 1)
Retinal achromic patch
Multiple renal cysts
Multiple pits or dents in the teeth
Fibromas (growths) of the gums inside the mouth
Multiple kidney cysts
Pale discolorations in the skin, called “confetti.”
Changes in the retina inside the eye
Hamartomas, which are benign tissue growths
Definitive diagnosis is established in patients with two major features or one major feature with at least 2 minor features, while “possible diagnosis” is recognized in patients with one major feature or at least 2 minor features.[rx][rx]
Diagnosis of Tuberous Sclerosis Complex
Diagnosing TSC is based upon clinical criteria. The first clue may be the presence of seizures or delayed development. In other cases, the first sign may be white patches on the skin (hypomelanotic macules) or the identification of cardiac tumor rhabdomyoma.
Diagnosis of the disorder is based on a careful clinical exam in combination with computed tomography (CT) or magnetic resonance imaging (MRI) of the brain—which may show tubers in the brain, and an ultrasound of the heart, liver, and kidneys, which may show tumors in those organs. Doctors should carefully examine the skin for a wide variety of skin features, the fingernails, and toenails for ungual fibromas; the teeth and gums for dental pits and/or gum fibromas; and the eyes for retinal lesions. A small hand-help lamp that uses black light, otherwise known as ultraviolet light, may show hypomelanotic macules which are sometimes hard to see on infants and individuals with pale or fair skin. A doctor experienced in the diagnosis of TSC should evaluate a potential patient.
In infants, TSC may be suspected if the child has cardiac rhabdomyomas at birth or seizures (especially the kind called infantile spasms) in the first six months of life. With a careful examination of the skin and brain, it may be possible to diagnose TSC in a very young infant. However, many children are not diagnosed until later in life when their seizures begin and other symptoms such as facial angiofibromas appear.
Treatment of Tuberous Sclerosis Complex
mTOR inhibitor medicines – can be used to treat brain tumours, kidney tumours and epilepsy caused by TSC
anti-epileptic medicines – to treat the associated seizures. Medication needs to be carefully monitored to make sure the child isn’t over-sedated
brain surgery – if seizures cannot be controlled, it may be possible to remove lesions in the brain to reduce seizures
skin treatments – dermatologists can provide advice on both surgical and medical treatment for the skin signs of TSC, including mTOR inhibitor creams.
occupational therapy – can help children acquire skills and strategies
speech therapy – can assist communication skills.
There is no cure for TSC, although treatment is available for a number of the symptoms. Antiepileptic drugs may be used to control seizures. Vigabatrin is a particularly useful medication in TSC and has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of infantile spasms in TSC, although it has significant side effects. The FDA has approved the drug everolimus (Afinitor®) to treat subependymal giant cell astrocytomas (SEGA brain tumors) and angiomyolipoma kidney tumors, in addition to intractable seizures (seizures not controlled well by medicine). Specific medications may be prescribed for behavior problems. Intervention programs including special school programs and various therapies (such as physical, occupational, and speech therapies) may benefit individuals with special needs and developmental issues. Surgery may be needed in case of complications connected to tubers, subependymal nodules, or SEGA, as well as in risk of hemorrhage from kidney tumors. Respiratory insufficiency due to LAM can be treated with supplemental oxygen therapy or lung transplantation, if severe.
Skin lesions, particularly facial angiofibromas, may be psychologically distressing for some patients. Laser treatment or electrosurgery can be used to remove angiofibroma.
The topical mTOR inhibitor sirolimus 0.2% gel (also called rapamycin) has proved helpful in reducing angiofibromas in a clinical trial involving 36 adults and children. One study has also reported improvement in hypopigmented macules. A larger prospective, multicentre, randomized, double-blind, vehicle-controlled trial enrolled 179 patients with tuberous sclerosis-related facial angiofibromas and found improvement in more than 80% of patients treated with topical 1% rapamycin with most occurring in the first month.
Infantile spasms are best treated with vigabatrin and adrenocorticotropic hormone used as a second-line therapy. Other seizure types have no TSC-specific recommendation, though epilepsy in TSC is typically difficult to treat (medically refractory).
Treatment may require the coordinated efforts of a team of specialists. Pediatricians and general internists, neurologists, dermatologists, cardiologists, dental specialists, eye specialists, psychiatrists, and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment. Genetic counseling will be of benefit for affected individuals and their families.
The treatment for tuberous sclerosis is supportive and symptomatic. Early developmental intervention is important to ensure that affected children reach their potential. Most affected children will benefit from occupational, physical and speech therapy. Various methods of rehabilitative and behavioral therapy may be beneficial. It is essential that therapies are continued on a year-round basis to promote development of new skills and to prevent regression. Additional medical, social and/or vocational services including special remedial education may be necessary. Psychosocial support for the entire family is essential as well.
Anti-seizure drugs (anticonvulsants) may be prescribed to control seizures. The specific drug that is used will depend on several factors including the specific type of seizure, an affected individual’s age, other organ systems that are affected, and the severity of symptoms. Conventional anticonvulsants drugs that may be administered include phenobarbital, Dilantin (phenytoin), Klonopin (clonazepam), Depakene/Depakote (valproic acid/divalproex sodium), Tegretol (carbamazepine), Trileptal (oxcarbazepine), Topamax (topiramate), Lamictal (lamotrigine), Zonegran (zonisemide), Vimpat (lacosamide), Banzel (rufinamide), Onfi (clobazam), and others. All these anticonvulsants have potential side effects and require careful monitoring by a physician.
Two drugs have been approved by the U.S. Food and Drug Administration (FDA) specifically for the treatment of seizures associated with tuberous sclerosis. FDA approved Afinitor (everolimus) for the treatment of seizures in adult and pediatric patients aged 2 years and older with tuberous sclerosis in 2018, and Epidiolex (cannabidiol) for patients one year and older in 2020.
Sabril (vigabatrin) was approved in 2009 by the FDA to treat infantile spasms in children ages 1 month to 2 years. Treatment of children with tuberous sclerosis and infantile spasms with vigabatrin has been found to be effective. Visual field loss is an important safety concern with the use of this medication. The FDA has also approved adreno-corticotrophic hormone or ACTH (Acthar gel) for the treatment of infantile spasms. This medication has also been used to treat infants with tuberous sclerosis. These medications are used cautiously because of their side effects.
No specific anti-seizure medication works for all affected individuals. Often, a combination of different drugs may be required to treat some individuals. Alternative treatments include the ketogenic diet or the glycemic diet. Sometimes, seizures can be difficult to treat and medications or diets that initially worked will no longer provide benefit (refractory seizures). In some instances, seizure surgery to remove areas of brain dysplasia may be necessary to help to control seizures that don’t respond or stop responding to medications. Less invasive surgical options to control seizures include the implanting of a vagal nerve stimulator (VNS device). This is a small electrical stimulator placed under the skin over the upper chest and connected to one vagal nerve in order to provide intermittent electrical stimulus, like a pacemaker to the brain.
Surgery of other organs may be necessary if the ability of a particular organ to function properly is impaired by the presence of a tumor. For example, the obstruction of cerebrospinal fluid (CSF) circulation inside the brain (intracranial hypertension) because of a benign tumor may require a shunting procedure to drain the liquid or the surgical removal of the tumor.
In 2012, the FDA approved the use of Afinitor (everolimus) for the treatment of children and adults with tuberous sclerosis who have a subependymal giant cell astrocytoma that cannot be removed or can be only partially removed by surgery. The FDA also approved everolimus for the treatment of adults with tuberous sclerosis who have an angiomyolipoma of the kidney that does not require surgery right away. In some instances, angiomyolipomas will require surgery or embolization therapy. Cutting off the blood supply (arterial embolization) to a kidney tumor may be used to shrink down the size of the tumor. Embolization is usually followed by treatment with corticosteroids and surgical removal (resection) of the tumor that spares the kidney or by destruction (ablation) of the tumor. Large cystic lesions of the kidneys may also require surgical decompression or removal.
In suspected or newly diagnosed TSC, the following tests and procedures are recommended by 2012 International Tuberous Sclerosis Complex Consensus Conference.[rx]
Take a personal and family history covering three generations. Genetic counseling and tests determine if other individuals are at risk.
A magnetic resonance imaging (MRI) of the brain to identify tubers, subependymal nodules (SEN) and sub-ependymal giant cell astrocytomas (SEGA).
Children undergo a baseline electroencephalograph (EEG) and family educated to identify seizures if/when they occur.
Assess children for behavioral issues, autism spectrum disorder, psychiatric disorders, developmental delay, and neuropsychological problems.
Scan the abdomen for tumors in various organs, but most importantly angiomyolipomata in the kidneys. MRI is superior to CT or ultrasound. Take blood pressure and test renal function.
In adult women, test pulmonary function and perform a high-resolution computed tomography (HRCT) of the chest.
Examine the skin under a Wood’s lamp (hypomelanotic macules), the fingers and toes (ungual fibroma), the face (angiofibromas), and the mouth (dental pits and gingival fibromas).
In infants under three, perform an echocardiogram to spot rhabdomyoma, and electrocardiogram (ECG) for any arrhythmia.
Use a fundoscopy to spot retinal hamartomas or achromic patches.
A benign tumor inside the heart (rhabdomyoma) may not cause symptoms and generally does not require treatment as they often regress on their own within the first several years after birth. If symptomatic, however, surgical removal (resection) may be necessary. Reports in the medical literature have detailed the off-label use of mTOR inhibitors to treat these tumors with positive results. Some affected individuals may be prescribed certain medications to treat irregular heartbeats (arrhythmias).
Individuals taking mTOR inhibitors for internal tumors (e.g. SEGAs or angiomyolipomas) may see improvement in skin lesions. Topical formulations of mTOR inhibitors have shown promise in treating facial angiofibromas. Individuals with no immediate indication for mTOR inhibitor treatment may undergo certain procedures to improve the appearance of skin lesions including dermabrasion, laser therapy, or surgical removal (excision) of a lesion.
In 2015, the FDA approved the use of mTOR inhibitors for the treatment of lung complications such as LAM in individuals with tuberous sclerosis. Because LAM occurs most often in young women of childbearing age, researchers have speculated that female hormones such as estrogen play a role in the development of the disorder. A link between LAM and female hormones has not been proven. However, many physicians have explored the use of agents that lower the production or effects of estrogen in the body. The results have varied greatly among individuals. Such agents may include medroxyprogesterone acetate. Estrogen-containing medications and dietary supplements should be discontinued in patients with LAM.
Supplemental oxygen therapy may be necessary for some individuals with impaired lung function. In individuals with severe lung disease that is resistant to treatment, a lung transplant may ultimately become necessary.
Because TSC is a lifelong condition, individuals need to be regularly monitored by a doctor to make sure they are receiving the best possible treatments. Due to the many varied symptoms of TSC, care by a clinician experienced with the disorder is recommended.
Basic laboratory studies have revealed insight into the function of the TSC genes and have led to use of rapamycin (mTOR) inhibitors and related drugs for treating some of the manifestations of TSC.
- Surgery. If a growth affects the ability of a specific organ — such as the kidney or heart — to function, the growth may be surgically removed. Sometimes surgery helps control seizures caused by brain growths that don’t respond to medication. Surgical procedures such as dermabrasion or laser treatment may improve the appearance of skin growths.
- Various types of therapy. Early intervention services, such as occupational, physical or speech therapy, can help children with tuberous sclerosis who have special needs in these areas improve their ability to manage daily tasks and activities.
- Educational and vocational services. Early intervention and special needs services can help children with developmental delays and behavior issues adapt to the classroom so that they can meet their full potential. When needed, social, vocational and rehabilitation services may continue throughout life.
- Psychiatric and behavior management. Talking with a mental health provider may help children accept and adjust to living with this disorder. A mental health provider can also help address behavioral, social or emotional issues and recommend resources.
Tuberous sclerosis is a lifelong condition that requires careful monitoring and follow-up because many signs and symptoms may take years to develop. A schedule of regular follow-up monitoring throughout life may include tests similar to those done during diagnosis. Early identification of problems can help prevent complications.
What is the prognosis?
The prognosis for individuals with TSC is highly variable and depends on the severity of symptoms. Those individuals with mild symptoms usually do well and have a normal life expectancy, while paying attention to TSC-specific issues. Individuals who are severely affected can suffer from severe mental retardation and persistent epilepsy.
All individuals with TSC are at risk for life-threatening conditions related to brain tumors, kidney lesions, or LAM. Continued monitoring by a physician experienced with TSC is important. With appropriate medical care, most individuals with the disorder can look forward to normal life expectancy.
Tuberous sclerosis complex is a genodermatosis:
Autosomal dominant with hamartomas that affect multiple organs.
Autosomal recessive with hamartomas that affect multiple organs.
Autosomal dominant predominantly affecting females, and the most commonly affected organs are skin, central nervous system, heart, lungs and kidneys.
Autosomal recessive with vascular malformations in many organs, being the most affected skin and central nervous system.
The classical tuberous sclerosis triad is characterized by:
Shagreen patch, facial angiofibromas and mental retardation.
Epilepsy, sebaceous adenoma and shagreen patch.
Facial angiofibromas, fibrous cephalic plaque and epilepsy.
Mental retardation, epilepsy and sebaceous adenoma (angiofibroma).
Choose the sentence with the correct sequence:
( ) Skin lesions are found in more than 90% of cases, the majority appearing in the 3rd decade of life.
( ) “Ash-leaf” lesions tend to follow Blaschko lines when on the trunk, typical for type 3 mosaicism.
( ) Hypopigmented macules in “confetti” or guttate leukoderma are hypopigmented macules that appear over the years.
( ) Hypopigmented macules are many times found since birth, allowing for the early diagnosis of the disease when associated to other clinical findings.
F T T F
F F F T
T T F T
F T F T
About connective tissue nevi and ungual fibromas or Koenen tumors, it is correct to say that:
Connective tissue nevi seen in TSC are normal-colored to brown plaques restricted to the lumbosacral region.
Shagreen patch many times have the aspect of orange peel and are found on the upper back.
Fibrous cephalic plaque is present in more than 80% of cases, being most commonly found on one side of the forehead.
Koenen tumor usually appears during adolescence and has a predilection for females and the toes.
According to the systemic manifestations of TSC, we can affirm that the correct items are:
Angiomyolipomas increase progressively from infancy and stop growing in the elderly.
Renal lesions have an indolent, clinically asymptomatic course, with no potentially severe repercussions in the patient’s life.
In cases of patients that evolve with hematuria in adulthood, the possibility of malignant transformation of the angiomyolipomas must be kept in mind, since they are usually asymptomatic.
Lymphangioleiomyomatosis affects predominantly younger women with the first manifestations after early adolescence.
Rhabdomyoma is the most common cardiac tumor and tends to grow progressively in the first year, when it stabilizes and continues until adulthood.
1 – 3
2 – 4
3 – 5
1 – 4
Choose the INCORRECT option:
The identification of the pathogenic TSC1 or TSC2 DNA mutation is not enough to establish the diagnosis of TSC.
Molecular testing yields a positive result in 75% to 90% of TSC patients.
In 10% to 25% of patients, conventional genetic testing does not identify the pathogenic TSC1 or TSC2 mutation.
The identification of the pathogenic mutation for TSC in conventional genetic testing configures an independent diagnostic criterion.
About the diagnostic criteria for the tuberous sclerosis complex, reviewed in 2012, in the second International Tuberous Sclerosis Complex Consensus Conference, all are included as extracutaneous manifestations, EXCEPT:
Subependymal giant cell astrocytoma.
Pigmented hamartomas of the iris.
It is a MAJOR clinical criterion for the diagnosis of TSC:
≥ 5 hypopigmented macules with at least 3mm diameter.
≥ 3 facial angiofibromas.
≥ 2 intraoral fibromas.
> 3 dental enamel pits.
From the dermatological point of view, many destructive or surgical treatment options are used to reduce the development of and remove facial angiofibromas. It is correct to say that:
The destructive procedures are usually comfortable for the patient and can be performed at any age.
It usually is not necessary to repeat laser treatments periodically because the lesions tend not to recur.
Are therapeutic options for facial angiofibromas dermabrasion, surgical excision, electrocautery and laser.
It is not necessary to combine therapeutic methods to optimize results since that regardless of the treatment chosen, all provide satisfactory results.
Diagnostic suspicion of TSC comes from the following findings, EXCEPT:
Antenatal detection of cardiac rhabdomyomas.
Post-natal identification of hypopigmented patches on the skin.
Visualization of ephelis on the axillary or inguinal regions.
Seizures in childhood, particularly with spasms.