What is TSC?
Tuberous sclerosis complex (TSC), is a rare genetic disease that causes non-cancerous (benign) tumours to grow in different areas of the body, most commonly the brain, kidneys, skin, heart, and lungs. The severity of the condition can vary widely and affects everybody differently. In some people the disease is very mild, while others may have serious manifestations. It is a progressive disease, and symptoms emerge and change through the person’s lifetime.
There is no cure, and treatment relies on symptom management for which there are international clinical consensus recommendations. Considerable progress has been made in treatments in recent years and the prognosis of somebody with TSC is continuously improving. TSC has a global live birth prevalence of approximately 1:6000-1:10000.
Receiving a diagnosis of Tuberous Sclerosis Complex (TSC) may be overwhelming for you and your family. We hope this website & booklet, compiled by parents of children with TSC, and healthcare professionals, will help you through this difficult time.
Signs, Symptoms & Management of Tuberous Sclerosis Complex (TSC)
TSC affects no two people in the same way. They may experience physical/ psychiatric/psycholgical symptoms, ranging from mild to severe. There is no way predict with certainty how the disorder will manifest and progress.
The diagnosis of TSC can be made based on clinical manifestations or genetic testing. However, genetic testing is recommended in all cases, and accurate diagnosis is critical to the surveillance and management of the disease. International consensus recommendations for the diagnosis, surveillance, and management of TSC exist.
Below are the consensus clinical diagnostic, surveillance & management guidelines for the physical and Tuberous Sclerosis Associated Neuropsychiatric (TAND) symptoms.
To better understand the potential symptoms, click below on the organs most often affected. For Information about Tuberous Sclerosis Neuropsychiatric Disorders (TAND), there is a specific section below and direct link.
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Several types of brain lesions are seen in individuals with Tuberous Sclerosis Complex (TSC); some people will have all the lesions, whereas others will have no brain involvement at all.
Cortical Tubers (from which TSC is named) can be thought of as a “birth defect” on the brain. ‘Tuber’ is Latin for swelling and ‘skleros’ is Greek for hard. They are small areas in the cortex (the outer layer of the brain) that do not develop normally. Tubers can be seen as early as 20 weeks’ gestation and the number of tubers in the brain of individuals with TSC stays the same throughout their life. Tubers are best seen by magnetic resonance imaging (MRI). It is thought that the presence of cortical tubers, and the areas around them, disrupts the normal “wiring” of the brain and causes seizures in individuals with TSC.
Subependymal nodules (SENs) Subependymal nodules (SEN) are groups of cells forming nodules < 1 cm, found on the walls of the cerebral ventricles ( natural cavities in the brain which contain Cerebro spinal fluid CSF) and seen in 80% of TSC patients. They are visible within the first 6 months of life and are frequently asymptomatic. They grow in proportion to the tissue around them and can calcify with age. However, in 20% of patients they may develop into subependymal giant cell astrocytoma (SEGAs) and can cause serious complications, They are not believed to be directly responsible for neurological problems. The word ‘subependymal’ refers to their location below the ependyma.i.e., the membrane lining the ventricles inside the brain.
SENs can calcify with age. Because of this calcification, they can be easily detected with a computed tomography (CT) scan. If they have not calcified, they may not be seen on CT images but will be seen on Magnetic Resonance Imaging (MRI).
Subependymal giant cell astrocytomas (SEGAs). SEGAs can develop in up to 20% individuals with TSC. Typically, SEGAs do not occur in very young children but grow during childhood with the chance for their growth decreasing after 20yrs of age.
SEGAs are found in the ventricles in the brain. Ventricles are natural spaces inside the brain filled with a clear fluid called cerebrospinal fluid (CSF). SEGAs are non-cancerous, however, they can be problematic because they may grow large enough to block the flow of CSF within the brain. This causes increased pressure within the brain(hydrocephalus) and people with TSC can become very unwell and require surgical intervention. Symptoms include vomiting, nausea, and headaches as well as changes in appetite, behaviour, and mood. These symptoms may or may not signal growth of a tumour, but indicates that there may be a problem and that the child should be seen by a physician.
Brain imaging should be done at the time of diagnosis to get a baseline image and then according to International Consensus Guidelines, (usually every 1 to 3 years afterward).
The most common effect of brain manifestation is epilepsy or seizures occurring in approximately 85% of individuals diagnosed with TSC and Tuberous Sclerosis Complex Neuropsychiatric disorders (TAND) occurring in over 90%.
Epilepsy/seizures and Tuberous Sclerosis Complex Neuropsychiatric disorders (TAND) which include behavioural, psychiatric, intellectual, learning, neuropsychological and psychiatric challenges, are dealt with separately. (from which TSC is named) can be thought of as a “birth defect” on the brain. ‘Tuber’ is Latin for swelling and ‘skleros’ is Greek for hard. They are small areas in the cortex (the outer layer of the brain) that do not develop normally. Tubers can be seen as early as 20 weeks’ gestation and the number of tubers in the brain of individuals with TSC stays the same throughout their life. Tubers are best seen by magnetic resonance imaging (MRI). It is thought that the presence of cortical tubers, and the areas around them, disrupts the normal “wiring” of the brain and causes seizures in individuals with TSC.
Subependymal nodules (SENs) Subependymal nodules (SEN) are groups of cells forming nodules < 1 cm, found on the walls of the cerebral ventricles ( natural cavities in the brain which contain Cerebro spinal fluid CSF) and seen in 80% of TSC patients. They are visible within the first 6 months of life and are frequently asymptomatic. They grow in proportion to the tissue around them and can calcify with age. However, in 20% of patients they may develop into subependymal giant cell astrocytoma (SEGAs) and can cause serious complications, They are not believed to be directly responsible for neurological problems. The word ‘subependymal’ refers to their location below the ependyma.i.e., the membrane lining the ventricles inside the brain.
SENs can calcify with age. Because of this calcification, they can be easily detected with a computed tomography (CT) scan. If they have not calcified, they may not be seen on CT images but will be seen on Magnetic Resonance Imaging (MRI).
Subependymal giant cell astrocytomas (SEGAs). SEGAs can develop in up to 20% individuals with TSC. Typically, SEGAs do not occur in very young children but grow during childhood with the chance for their growth decreasing after 20 years of age.
SEGAs are found in the ventricles in the brain. Ventricles are natural spaces inside the brain filled with a clear fluid called cerebrospinal fluid (CSF). SEGAs are non-cancerous, however, they can be problematic because they may grow large enough to block the flow of CSF within the brain. This causes increased pressure within the brain(hydrocephalus) and people with TSC can become very unwell and require surgical intervention. Symptoms include vomiting, nausea, and headaches as well as changes in appetite, behaviour, and mood. These symptoms may or may not signal growth of a tumour, but indicates that there may be a problem and that the child should be seen by a physician.
Brain imaging should be done at the time of diagnosis to get a baseline image and then according to International Consensus Guidelines, (usually every 1 to 3 years afterward).
The most common effect of brain manifestation is epilepsy or seizures occurring in approximately 85% of individuals diagnosed with TSC and Tuberous Sclerosis Complex Neuropsychiatric disorders (TAND) occurring in over 90%.
Epilepsy/seizures and Tuberous Sclerosis Complex Neuropsychiatric disorders (TAND) which include behavioural, psychiatric, intellectual, learning, neuropsychological and psychiatric challenges, are dealt with separately.
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Over 50% of people with TSC may have signs of TSC in their eyes. Vision loss is NOT common in TSC.
Retinal Hamartomas
There are three types of benign tumours (hamartomas) which can occur on the retina in TSC.
Smooth-surfaced hamartoma, modular or “mulberry” hamartoma and transitional or mixed hamartoma that shows characteristics of both of these.
The frequency of retinal hamartomas in individuals with TSC has varied in reports from almost negligible to 87 percent of individuals, a difference probably reflecting the technique used and the expertise of the examiner.
Retinal lesions may be difficult to identify without papillary dilation and indirect ophthalmoscopy, particularly difficult to examine in uncooperative children. Most retinal hamartomas remain dormant, although occasionally individuals with TSC have visual impairment resulting from a large hamartoma in the macular region. Instances of visual loss following retinal detachment, vitreous haemorrhage, or hamartoma enlargement are rare.
The retinal hamartomas are benign and usually do not change over time. For the most part, treatment of the retinal lesions and repeated ophthalmologic examinations are unnecessary. Normal eye care should be maintained.
Optic Disc Hamartomas
These are benign hamartomas involving the optic nerve. Although less common than the retinal hamartoma, a defect in the pigment of the iris has also been observed in some individuals with TSC.
Retinal Hypopigmented Lesions
White depigmented patches, reminiscent of the hypopigmented macules on the skin, have also been observed on the retina of some individuals with TSC.
Angiofibroma Near the Eyes
Facial angiofibroma can grow near the eyes or on the eyelids, however this is rare.
Vision Problems
Cortical visual impairment (CVI) is the term used when the brain encounters difficulties in processing information received from the eyes . It can occur in some people with severe seizures or brain tumours.
If a SEGA becomes large and blocks the ventricle, vision can be affected and requires urgent medical care. This is a rare occurrence.
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Epilepsy is derived from the Greek word ‘epilambanein’ and means to be seized or overwhelmed by surprise. A ‘seizure’ is caused by the hyper-synchronous discharge of neurons (abnormal, excessive synchronization of electrical activity among a large population of neurons ) in the brain causing an alteration of neurological function. Epilepsy exists when the individual has epileptic seizure and the brain displays ‘a pathological and enduring tendency to have recurrent seizures’.
All seizure types such as tonic, atonic, tonic-clinic can be seen in patients with TSC and can begin any time from childhood into adulthood. It is known that up to 12% of patients with TSC can develop epilepsy as adults.
There are several therapeutic options available for the treatment of all epilepsy types, including antiepileptic drugs (AEDs), hormonal treatment, ketogenic diet, epilepsy surgery and vagus nerve stimulation and in more recent studies, the use of mTOR inhibitors.
In TSC patients, epilepsy is often observed in the first months of life and in most cases within the first two years. At this age, epilepsy usually presents as focal seizures with or without infantile spasms, and about two thirds of TSC patients are reported to develop refractory epilepsy (drug resistant epilepsy) which is associated with intellectual disability and neuropsychiatric disorders known as Tuberous Sclerosis Associated Neuropsychiatric Disorders (TAND).
It is crucial to recognise seizures at an early stage in order to commence antiepileptic treatment and improve long-term outcomes and reduce intellectual disability.
Epilepsy Ireland offers information and a wide range of services to support people with epilepsy.
Visit Tuberous Sclerosis Australia for information on the different types of seizures
Infantile spasms (IS) are a medical emergency. They are a serious type of seizure occurring in infancy which can cause catastrophic and permanent damage to a child’s brain. IS last around one to two seconds in a series and more often after waking up. They include repetitive but often subtle movements – including jerking of the mid-section, dropping of the head, raising of the arms or wide-eyed blinks. Unfortunately infantile spasms can often be overlooked or misdiagnosed for other conditions, including colic, reflux, or a startle reflex.In 90% of cases they occur in infants less than 12 months of age and are more usually diagnosed between four and eight months, however, they can occur up to 2 years of age. The presence of infantile spasms can be an early indicator of TSC and are a common neurological manifestation of TSC and it is estimated that up to 50% of infants may experience them. Outcomes can vary dependent on the promptness of identifying the spasms and prioritising treatment. Global delays across learning and development as well as specific learning and developmental difficulties can be an impact of the spasms, which is why it is so important to have an early diagnosis and to start treatment immediately.
Please see this video:
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Non-cancerous TSC tumours in the heart are called Cardiac rhabdomyomas. They rarely cause symptoms and decrease in size during childhood. The incidence varies from 47% to 67%. They are sometimes seen on ultrasound during pregnancy, the first clinical sign that the baby has TSC.
Most rhabdomyomas of the heart are asymptomatic, however, for some people symptoms can occur and depend on the number, size and location. Large tumours can obstruct blood flow through the heart causing decreased blood flow to different organs including the lungs. When a rhabdomyoma is close to the heart’s electrical system, an abnormal rhythm (arrhythmia) can occur, the most common being Wolff Parkinson White (WPW). Large rhabdomyoma in the heart muscle can cause impaired heart muscle function or cardiomyopathy. A small number of people with rhabdomyoma may have a heart murmur.
Cardiac evaluation and screening is recommended for all patients with TSC. Foetal echocardiography should be considered when rhabdomyomas are identified by prenatal ultrasound. People should be treated by an experienced cardiologist if an abnormal rhythm (arrhythmia) or other cardiac problem is present.
More frequent or advanced diagnostic assessment may be required for symptomatic patients. Patients who have significant arrhythmias may require treatment with medication or a special cardiac catheterisation procedure.
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The majority of individuals (greater than 80%) with tuberous sclerosis complex (TSC) will develop some form of renal (kidney) disease during their lifetime. There are three main renal disorders in TSC: renal cysts, renal angiomyolipoma and renal cell carcinoma.
Renal angiomyolipomas, are usually the greatest concern in TSC. The blood vessels within angiomyolipomas are abnormal and can develop weak spots in their wall, called aneurysms, that can burst and lead to bleeding. Renal angiomyolipomata occur in approximately 80% of TSC patients. Most of the time both kidneys are involved.
Renal cysts are often small, benign fluid filled “holes” in the kidney that occur in about 50 percent of individuals with TSC. These cysts, though not common, can lead to elevated blood pressure, but usually do not cause discomfort. Sometimes the kidney is filled with cysts, and this can lead to kidney impairment and even kidney failure, requiring dialysis or transplantation.
Renal cell carcinoma (cancerous tumours of the kidney), although rare in TSC, must be kept in mind.
The current methods used to diagnose these renal abnormalities include renal ultrasonography, CT scanning and magnetic resonance imaging (MRI). These are all non-invasive procedures that are available in almost every major hospital. The renal ultrasound provides the least detailed image of the kidney, while the MRI provides the most detailed. In general, the ultrasound is sufficient to detect both renal cysts and fat-containing angiomyolipomas, but may not provide enough detail to accurately measure and follow the renal lesions and can miss lesions that lack the fat component.
The kidneys should be scanned, preferably with MRI, at the time of diagnosis, and at 2-3 year intervals if no cysts or angiomyolipomas are identified. If kidney lesions are identified, then the growth of these lesions should be followed using repeated MRI every year or two, unless symptoms develop or the lesion has an unusual growth pattern. Imaging is critical to assess if kidney lesions are present and/or if there has been a change in any of the existing kidney lesions.
Renal angiomyolipomas—made up of vascular tissue (angio), smooth muscle (myo), and fat (lipoma)—are benign hamartomas. These hamartomas are well circumscribed groups of cells that multiply excessively, growing as tumours that may or may not cause symptoms. The prevalence of TSC-related renal angiomyolipomas increases with age, and in adults bilateral tumours or multiple tumours in one kidney are common. Angiomyolipomas begin in childhood in many individuals with TSC, but they usually grow very slowly and may not be problematic until young adulthood. Individuals with TSC should have their kidneys imaged at the time of diagnosis and then regularly throughout their lives.
TSC renal cysts are commonly multiple and bilateral. They are the second most frequently occurring kidney manifestation of TSC. Single or multiple renal cysts occur less often in individuals with TSC than do angiomyolipomas, but they may appear earlier. Some cysts may collapse and disappear.
TSC renal cysts are commonly multiple and bilateral. They are the second most frequently occurring kidney manifestation of TSC. Single or multiple renal cysts occur less often in individuals with TSC than do angiomyolipomas, but they may appear earlier. Some cysts may collapse and disappear.
One important research finding was the discovery of the TSC2 gene in close proximity to the gene for polycystic kidney disease (PKD1) on chromosome 16. A small group of individuals with TS have a large segment of chromosome 16 deleted which means that both the TSC2 and PKD1 genes are also removed. These individuals most often will have polycystic kidneys from birth and will require close monitoring and treatment throughout the childhood years.
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The main lung lesion found in TSC is lymphangioleiomyomatosis (LAM). LAM occurs almost exclusively in women and in TSC. Some studies estimated that LAM will occur in 80% of women with TSC. Lung involvement in tuberous sclerosis complex (TSC) has been identified for many years. In 2000-2001, three studies reported that between 26% and 39% of women with a diagnosis of TSC have lymphangioleiomyomatosis (LAM) (Costello et al., 2000; Franz et al., 2001; Moss et al., 2001). Several subsequent studies suggested that the frequency of lung involvement in adult women with TSC may be higher than previously suspected, ranging from 42% to 49% (Muzykewicz et al, 2009; Adriaensen et al, 2011; Cudzilo et al., 2013). Fortunately in many of these women, the disease does not cause significant respiratory symptoms. Due to the frequency of lung involvement in TSC, the recent TSC Consensus Conference report recommended that all women age 18 years and older with TSC should have a computerised tomography (CT) scan of the chest and pulmonary function testing. (Krueger et al., 2013).
The first symptoms of lung involvement in an individual with TSC may be shortness of breath after mild exercise, spontaneous coughing. Progression to lung failure may develop, but not usually until the third or fourth decade of life, if at all. Lung involvement in TSC can be severe, and some individuals will require lung transplantation.
If pulmonary involvement is noted, the individual should be monitored closely and should have repeated chest scans as needed.
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Individuals with Tuberous Sclerosis Complex (TSC) often see the disease manifested in the skin, including on the face, body and nails. In some cases, skin growths can become obtrusive but in most cases, the growths themselves are harmless. However manifestations such as facial angiofibromas can have a social impact and treatments are available.
Skin lesions resulting from TSC include:
hypomelanotic macules—patches of skin lighter than the surrounding skin (can be any size or shape or may be the classic “ash-leaf” shape)
shagreen patch—a patch of skin that is tough and dimpled like an orange peel
periungual or subungual fibromas—fibrous growths that appear around the fingernails and toenails;
facial angiofibromas—tumours of the face. Fibrous plaques sometimes appear on the forehead of individuals with TSC. There may also be fibrous, hairless scalp plaques surrounded by thin, white tufts of hair.
At the initial testing, the doctor uses a Wood’s lamp (an ultraviolet light) to better visualise the hypomelanotic macules—white patches on the skin that often are difficult to see, especially on infants and people with very pale skin. The entire body should be examined. The skin should be carefully examined for the other skin manifestations of TSC as well. Some of the skin signs may not be present at birth; the facial angiofibromas do not usually appear until between the ages of 3 and 5 at the earliest, and the periungual and subungual fibromas do not usually occur until much later in life. Lesions that appear later should be noted and brought to the attention of the doctor.
The most often treated skin manifestations of tuberous sclerosis complex (TSC) are the facial angiofibromas and periungual and subungual fibromas. The facial angiofibromas can be treated with Rapamycin (Sirolimus) cream or by laser surgery.
Individuals with TSC are more susceptible to sunburn and should be careful about sun exposure and use a broad-spectrum sunscreen. These sunscreens protect against UVA and UVB and should have a sun protection factor (SPF) of at least 30. Sunscreen should be applied to all areas exposed to the sun, since tanning of surrounding skin will make the hypomelanotic macules more apparent.
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Apart from the physical manifestations of TSC, most individuals with Tuberous Sclerosis Complex (about 90%) are affected by a broad range of behavioural, psychiatric, intellectual, academic, neuropsychological and psychosocial difficulties. Examples include autism, ADHD, intellectual disability, anxiety and depressive disorders, and difficulties in scholastic skills. These problems often cause the greatest burden to individuals with TSC and their families. Unfortunately, they are often not identified or treated.
Here’s a two page family-focused introduction to the TAND consensus recommendations.
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People with TSC may have dental pits and an overgrowth of the gums (fibromas) meaning teeth and gum tissue are slightly different and will require a little more care to keep them healthy. The tooth enamel may have random surface pits which may cause decay to occur more easily. A dentist can repair enamel pits.
Regular dental cleanings and x-ray check-ups to catch decay early, usually on a 6-month interval, are important. Your dentist may recommend recalls more frequent than 6 months based on you/your child’s risk for cavities. Children’s dentists (pediatric dentists) are trained in providing care to children and adults who may need sedation or extra behavioural care. Hospital dentistry is also an option if a patient cannot tolerate the regular office setting.
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Cysts and tumours similar to those observed in the kidney sometimes appear in the liver, lung, pancreas, and ovaries. Biopsy of a suspicious lesion is recommended only when the lesion is unusually large, growing, causing symptoms, or exhibiting other suspicious characteristics. If they are symptomatic, they should be treated by the appropriate specialist and be removed if medically necessary.
