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Tuberous sclerosis

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Tuberous sclerosis



Introduction 

Tuberous sclerosis, also known as tuberous sclerosis complex, is a rare genetic condition that causes mainly benign (non-cancerous) tumours to develop in different parts of the body.

Tumours can develop on the skin and in the:


brain

heart

eyes

kidneys

lungs


There is currently no cure for the condition, but there is a range of treatments for many of the associated symptoms. New research has shown that medicines called mTOR inhibitors may have important benefits in the future.

 Associated conditions and complications 

The benign tumours that develop from tuberous sclerosis can cause a range of other associated health conditions and complications. These include:


epilepsy – a condition that causes seizures (fits)

intellectual impairment, such as below-average intelligence 

learning disabilities

behavioural problems, such as hyperactivity or autism (a developmental disorder that causes problems with language and social interaction)

skin abnormalities, such as patches of light-coloured or thickened skin, or red acne-like spots

heart problems

kidney disease

lung problems

hydrocephalus – a build-up of fluid on the brain


The range and severity of these conditions can vary significantly from person to person, even among members of the same family.

Some people with tuberous sclerosis do not have many symptoms and the condition has no real impact on their quality of life.

For others, the condition can severely affect their intellectual development or cause life-threatening complications such as lung failure, and they require lifelong care.

 What causes tuberous sclerosi s? 

Tuberous sclerosis is a rare condition that affects 1 in every 6,000 live births worldwide. The condition is caused by mutations (changes) in one of two genes:


the TSC1 gene

the TSC2 gene


As both of these genes are involved in regulating cell growth, it is thought that the mutations are responsible for causing multiple tumours to develop. 

In around a quarter of cases, a child inherits one of the mutated genes from one of their parents. In the other 75% of cases, these mutations occur for no apparent reason.

Both sexes and all ethnic groups are equally affected by tuberous sclerosis.

Outlook

The outlook for people with tuberous sclerosis depends on several main factors:


whether the mutation occurred in the TSC1 or TSC2 gene – people with a mutated TSC2 gene are more likely to have more serious and wide-ranging symptoms, such as epilepsy or multiple kidney tumours, although people with TSC1 may also experience severe symptoms

being born with low intelligence – children born with low intelligence usually have epilepsy that does not respond to medication, as well as associated behavioural problems such as autism or aggressive outbursts

how severely a child is affected at first – the severity of the condition is usually clear by the time a child is five years old

a new treatment – new medicines called mTOR inhibitors may improve the outlook 


Most people with tuberous sclerosis will live a normal lifespan, but a number of complications may develop that can be fatal.

People with epilepsy that is difficult to treat are at risk of a condition called sudden unexpected death in epilepsy (SUDEP). This affects about 1 in every 250 people with difficult epilepsy every year. Other serious problems include hydrocephalus, kidney or lung problems.

Symptoms of tuberous sclerosis 

The non-cancerous (benign) tumours caused by tuberous sclerosis can develop almost anywhere in the body.

However, the areas most commonly affected include the: 


brain – occurring in an estimated 9 out of 10 cases

skin – occurring in an estimated 9 out of 10 cases

kidneys – occurring in an estimated 8 out of 10 cases

heart – occurring in an estimated 7 out of 10 cases

eyes – occurring in an estimated 8 out of 10 cases 

lungs – occurring in an estimated 4 out of 10 cases in women


These are described in more detail below.

Neurological conditions and complications

Tumours that develop in the brain can affect its ability to function normally, and can cause a range of neurological conditions and complications. "Neurological" is a term used to describe the nervous system, which includes the brain.

Epilepsy

Epilepsy is the most common neurological symptom of tuberous sclerosis, affecting up to 9 out of 10 people with the condition. The condition causes repeated seizures (fits) and a temporary loss of consciousness.

Infantile spasms

Around a third of children will develop a more severe form of epilepsy known as infantile spasms. They usually develop during the first three months of life.

Infantile spasms occur when the baby has multiple seizures in a short space of time. Each seizure often only lasts for a few seconds. A baby usually has a "run" or "cluster" of around 20 seizures, although some babies can have up to 100 seizures over a short period of time.

Infantile spasms usually disappear by the time a child is three years old, but the condition often causes permanent brain damage. An estimated 7 out of 10 children who experience infantile spasms will go on to develop some degree of brain damage and impaired intelligence, such as very slow co-ordination or speech.

It is important to diagnose infantile spasms as early as possible as research has shown that early treatment can greatly improve the outlook of the condition.

Learning disabilities

Nearly half of all children with tuberous sclerosis will have a learning disability. In some cases, the learning disability could be quite mild. In other cases, it could be severe and result in profound disability.

Possible difficulties include: 


poor memory

low attention span

difficulty making plans or organising activities

learning much more slowly than other people


Behavioural and developmental disorders 

Around half of all children with tuberous sclerosis may also have behavioural or developmental disorders because of the way the condition affects their brain. These include: 


autistic spectrum disorders – a range of related developmental disorders that can cause problems with language, social interaction and behaviour

hyperactivity 

impulsive behaviour

aggression 

anxiety

extreme shyness

depression

schizophrenia – a condition that causes hallucinations and delusions (seeing or believing things that are not real or untrue) 

sleep disorders, such as finding it difficult to get to sleep or frequently waking up during the night, are common and often difficult to control; they can also be caused by epileptic seizures at night and may last for many years


Subependymal giant cell astrocytomas (SEGAs)

A small number of children with tuberous sclerosis will develop multiple types of brain tumours during brain development up until the age of five. These tumours then remain stable, but are thought to cause the other brain problems described above.

A small number of people develop large benign brain tumours. These are known as subependymal giant cell astrocytomas (SEGAs). SEGAs can develop at any age, but they most commonly occur after the teenage years.

In about 1 in 20 people who have these tumours the SEGAs grow too big and risk obstructing the flow of cerebrospinal fluid through the brain. Cerebrospinal fluid surrounds and protects the brain and spine.

If the flow of cerebrospinal fluid is blocked, it can cause pressure to build up in the brain. This is known as hydrocephalus. Symptoms can include:


headache

nausea and vomiting

lack of appetite

increased irritability, lethargy or drowsiness

personality changes

disorientation 

visual problems, such as double vision or blurred vision

fits and seizures

a sudden change in bladder or bowel control, such as urinary incontinence


In cases of hydrocephalus, emergency surgery is required to drain away excess fluid from the brain. If left untreated, hydrocephalus can cause brain damage or, in the most serious cases, death.

SEGAs can be picked up before they cause hydrocephalus through regular MRI scans. Pre-emptive treatment, such as an mTOR inhibitor or surgery, may be used to prevent problems occurring.

Skin lesions

Around 9 out of 10 of people with tuberous sclerosis will develop skin lesions. They usually occur during early childhood and can take the form of:


patches of light-coloured skin

areas of thickened skin

growths of skin under or around the nail


Red acne-like spots and blemishes are also common, especially on the face.

Kidney tumours

Up to 8 out of 10 children with tuberous sclerosis will develop multiple benign tumours inside their kidneys, usually by the age of five. The kidney tumours are called angiomyolipomas (AMLs) and are made up of blood vessels, muscle and fat.

Kidney tumours bigger than 3cm can rupture (split) and cause internal bleeding. This causes sudden pain and may require surgery. This is the most common kidney problem and occurs in up to two to three out of 10 people with tuberous sclerosis.

If the kidney tumours become too large, they can interfere with eating or occasionally with the workings of the kidneys. This can cause symptoms similar to kidney disease, such as:


tiredness

swollen ankles, feet or hands caused by water retention

shortness of breath

blood in the urine

protein in the urine 

an increased need to urinate, particularly at night

itchy skin

feeling sick


Polycystic kidneys

Some people with tuberous sclerosis are also born with polycystic kidneys. This is when multiple cysts (small fluid-filled sacs) develop in the kidneys.

Polycystic kidneys can cause symptoms of high blood pressure (hypertension) and kidney disease. Polycystic kidneys are also the most common cause of kidney failure in people with tuberous sclerosis, which occurs in 1 in 20 people. 

About two or three out of 10 children with tuberous sclerosis can also develop multiple simple cysts in their kidneys, but these kidney cysts usually cause no symptoms.

Kidney cancer

Less than 3 in 100 people with tuberous sclerosis will develop a type of kidney cancer called renal cell carcinoma

HeartToumer

Up to two-thirds of infants born with tuberous sclerosis will develop one or more tumours inside their heart. These tumours are usually very small and do not cause any symptoms. Unlike the other types of tumour caused by tuberous sclerosis, heart tumours will usually shrink and become much more difficult to detect as a child gets older.

However, in a small number of children, the tumours can block the flow of blood inside the heart or cause it to beat irregularly (arrhythmia).

Heart problems can also cause associated symptoms, including:


palpitations (an irregular heartbeat or the sensation of skipped or extra heartbeats)

dizziness

fainting

breathlessness

chest pains


Eye tumours

An estimated three-quarters of people with tuberous sclerosis will develop one or more tumours inside their eyes. The tumour grows on the surface of the retina, which is the thin layer of nerve cells that line the inside of the back of the eye. However, they rarely grow large enough to affect a person's vision.

Lung tumours

An estimated 40-60% of women with tuberous sclerosis will develop tumours and cysts inside their lungs. This is a condition called lymphangioleiomyomatosis (LAM). The condition usually develops at around 20 to 40 years of age. It is unclear why women are particularly vulnerable to lung tumours while men are rarely affected.

In most cases, these cysts and tumours do not cause a problem. Around half of all women with tuberous sclerosis may have lung tumours that show up when their lungs are scanned, but do not cause any symptoms.

However, around 1 in 20 women experience symptoms from their lung tumours. The tumours can cause shortness of breath and can feel like asthma. In some cases, one or more of the tumours can rupture, resulting in a collapsed lung. A collapsed lung can be life threatening. It occurs when air leaks out from inside the lung.

In the most serious cases, women with tuberous sclerosis and lung tumours can develop progressive lung failure.

Causes of tuberous sclerosis 

Tuberous sclerosis is caused by a genetic mutation that occurs in one of two genes.

The genes are:


the TSC1 gene

the TSC2 gene


Genetic mutations

Genetic mutations occur when the deoxyribonucleic acid (DNA) inside the gene changes. DNA stores genetic information and this genetic information is altered if the DNA changes, which can cause a genetic disorder.

Mutations are often inherited from a parent, or they can occur when a sperm or egg is made and a new mutation is created. Mutations can also occur if DNA is damaged by natural chemicals, including water and oxygen, or by radiation or sunlight, for example.

Someone with a new mutation will not have a family history of a condition, but they may be at risk of passing on the mutation to their children.

The TSC1 and TSC2 genes

Both of these genes are responsible for regulating cell growth. The genetic mutation is thought to affect the gene's ability to control cell growth properly, leading to multiple tumours throughout the body.

In around a quarter of cases of tuberous sclerosis, a child will inherit one of the mutated genes from one of their parents. If you are a parent who has one of the mutated genes, you have a one in two chance of passing it on every time you conceive a child. The severity of symptoms can often vary between an affected parent and an affected child.

In the other three-quarters of cases of tuberous sclerosis, the mutation occurs for no apparent reason. This is known as a spontaneous mutation. There is currently no way of identifying people who may be more likely to experience a spontaneous mutation.

The chances of getting tuberous sclerosis are the same for both sexes. All ethnic groups are equally affected by the condition.

Diagnosing tuberous sclerosis 

The length of time that it takes to make a successful diagnosis of tuberous sclerosis will depend on how severe a child's symptoms are.

For example, in a young child who quickly develops symptoms of epilepsy and kidney disease, tuberous sclerosis may immediately be suspected as an underlying cause. However, in children with few symptoms, a diagnosis may not be made until they develop patches on their skin, which can take several years.

Diagnostic checklist

Healthcare professionals use a checklist to help diagnose tuberous sclerosis. The checklist is made up of major and minor features. If a child has at least two major features, or one major and two minor features, it is likely that they have tuberous sclerosis.

The major features include:


three or more facial angiofibromas – benign (non-cancerous) growths on the back of the nose or upper throat

three or more patches of skin that are lighter than normal

two or more skin lesions that grow under or around the fingernails and toes

shagreen patches – a small area of raised skin with a texture similar to an orange peel, often found on the lower back

eye tumour(s)

brain tumour(s)

heart tumour(s)

lung tumour(s)

kidney tumour(s)


The minor features include:


more than three small pits in the teeth

two or more small lumps or tumours in the gums

nonrenal hamartomas – benign growths that do not affect the kidneys

retinal achromic patch – a small area of the retina that is lighter in colour than the area surrounding it 

"confetti" skin lesions on the face or body

several fluid-filled holes (cysts) affecting the kidneys 


Testing for tuberous sclerosis

A number of tests can also help confirm a diagnosis of tuberous sclerosis. These are:


an eye examination – eye tumours can often be the first sign of tuberous sclerosis

a skin examination – an ultraviolet light is often used to examine the skin as it can reveal skin lesions that have lost their colour (depigmented), or white patches

a magnetic resonance imaging (MRI) scan – these scans can often detect tumours within the brain

a computerised tomography (CT) scan or an ultrasound scan – these scans can often detect tumours within the kidneys, heart or lungs

an electroencephalogram (EEG) – a test that can detect abnormal electrical activity within the brain

an electrocardiogram (ECG) – a test that can detect abnormal electrical activity within the heart


Tuberous Sclerosis Association (TSA)

The Tuberous Sclerosis Association (TSA) provides information, advice and support to individuals and families affected by the condition.

You can visit the TSA website for more information and access to their online community. You can also contact the organisation's specialist advisers in your area.

Treating tuberous sclerosis 

Tuberous sclerosis is a lifelong condition that requires long-term care and support from a range of different healthcare professionals.

An individual care plan will be drawn up to address any needs or problems that your child has. As your child gets older, the plan will be reassessed to accommodate changes to their needs or situation.

Healthcare professionals

You and your child will also be assigned a key worker, who will be your point of contact with the various support services available. While your child is young, the key worker is likely to be a health visitor. However, as your child gets older and their needs become more complex, the key worker is likely to be a social worker.

Some of the other healthcare professionals involved in your or your child's care may include: 


an educational psychologist – who assists children having trouble progressing with their education as a result of emotional, psychological or behavioural problems

a neurologist – a specialist in treating conditions affecting the nervous system (the brain, nerves and spinal cord)

a cardiologist – a specialist in conditions that affect the heart 

an ophthalmologist – a medical doctor specialising in eye conditions

a genetic counsellor – to assess the risk of passing a genetic condition on to your children


Surveillance screening

Someone with tuberous sclerosis will require regular surveillance screening tests throughout their life. This is so the function of the organs most vulnerable to the condition, such as the brain, kidneys and lungs, can be regularly monitored and assessed.

Types of screening tests may include:


a magnetic resonance imaging (MRI) scan – to check for changes in tumours in the brain or kidneys

an ultrasound scan – this may also be used to check the kidney tumours

blood tests – to check how well the kidneys are working 

an echocardiogram – a test that uses sound waves to build up a picture of the heart

spirometry – a test to measure how much air a person can breathe out, and to check the function of the lungs


How often these tests are needed will depend on your or your child's age and the type of symptoms.

Epilepsy

Epilepsy is a very common feature of tuberous sclerosis. A number of medications known as anti-epileptic drugs (AEDs) have proved successful in preventing seizures in people with epilepsy.

Epilepsy medicines do not work as well for people with tuberous sclerosis, although many people with the condition can use them to control their seizures. If the first epilepsy medicine is not effective, the dose can be increased. You can also try a different medicine, or you may be prescribed two epilepsy medicines to take at once. 

Surgery for epilepsy

If epilepsy medicines are not effective, surgery for epilepsy may be considered.

In people with tuberous sclerosis, epilepsy is thought to be caused by tumours in the brain (epileptogenic tubers). You can have surgery to remove them, which may be an effective treatment for your epilepsy.

This type of surgery tends to be more successful if there are just one or two tumours. One study found more than two-thirds of children were seizure-free after having surgery.

However, not everyone with tuberous sclerosis is suitable for surgery. In some cases, no brain tumours can be found to explain the epilepsy.

Vagus nerve stimulation

An alternative to surgery for epilepsy is a treatment called vagus nerve stimulation (VNS). VNS involves surgically implanting a small electrical device similar to a pacemaker under the skin near the collarbone.

The device has a lead that is wrapped around the vagus nerve in the left side of the neck. The device stimulates the nerve by passing a regular dose of electricity through it. This can reduce the frequency and severity of the seizures.

If you feel the warning signs of a seizure, you can also activate an extra "burst" of stimulation. This can often prevent the seizure happening.

It is not fully understood exactly how and why VNS works, but it is thought that stimulating the vagus nerve alters chemical transmissions in the brain.

Behavioural and learning problems 

If your child is experiencing behavioural problems or has a learning disability, it is likely they will be referred to a psychologist. They will assess your child's learning ability and their likelihood of developing behavioural problems.

As part of the assessment process, a special educational needs plan may be drawn up. The plan is designed to provide the most effective type of education to meet your child's strengths and weaknesses.

Some children with tuberous sclerosis may also benefit from attending special educational centres. Others will be able to attend a mainstream school, but may need extra support during lessons.

mTOR inhibitors

Tuberous sclerosis causes tumours to grow in different parts of your body. For the tumours to grow, certain chemical reactions have to take place. Medicines that interrupt or block these chemical reactions may therefore be able to prevent the tumours growing.

New research is being carried out into medicines called mTOR inhibitors, which can block the chemical reaction that causes the tumours to grow.

There are two mTOR inhibitors: 


sirolimus 

everolimus


These have already been shown to shrink:


angiomyolipomas (AMLs) – the tumours in the kidneys made up of blood vessels, muscle and fat

subependymal giant cell astrocytomas (SEGAs) – the tumours in the brain; this may mean brain surgery would no longer be necessary 

lymphangioleiomyomatosis (LAM) – the tumours and cysts inside the lungs

facial angiofibromas – red skin lesions on the face


The mTOR inhibitors are also being tested to see if they can treat:


epilepsy

problems in the brain to do with thinking and learning 

behavioural problems caused by autistic tendencies


Treatments for the different types of tumours that tuberous sclerosis can cause are explained below.

Subependymal giant cell astrocytomas (SEGAs)

If one or more subependymal giant cell astrocytomas (SEGAs) are detected in the brain during routine screening, it may be necessary to surgically remove them. SEGAs are large non-cancerous brain tumours. If the SEGAs are not removed, they can cause a build-up of fluid on the brain (hydrocephalus). 

Everolimus

Some research has found that everolimus, a type of mTOR inhibitor, can shrink SEGAs in most people who take them. This prevents them causing hydrocephalus and can lead to fewer seizures (fits). This may reduce the need for brain surgery. More long-term studies are needed, but this may be a useful new treatment.

Skin lesions

Skin lesions do not usually present a serious health problem, but they can look unsightly and affect a person's confidence and self-esteem.

Laser therapy can successfully treat skin lesions. It involves using a focused beam of light to remove the lesions. The lesions can sometimes return, so repeated laser therapy sessions may be required. Using sun block is important as this protects the health of the skin long term.

Studies are now underway to test the effectiveness of the new mTOR inhibitors in treating skin rashes when used as a cream. Skin rashes also reduce if people are taking mTOR inhibitor tablets for kidney tumours.

Heart tumours

In most cases, heart tumours will not need treatment. Heart tumours in babies usually shrink as the child gets older, until they are barely detectable as adults. However, in some rare cases surgery may be required to remove the tumours if they begin to seriously affect the functioning of the heart.

Kidney tumours

If kidney tumours cause symptoms of high blood pressure (hypertension), medicine can be used to help lower it.

If individual kidney tumours continue to grow larger than 3cm, they can cause dangerous bleeding. The mTOR inhibitor everolimus is used to prevent growing kidney tumours that are not bleeding.

If they bleed, it may be possible to stop their growth using a process called embolisation. They can also be treated with an mTOR inhibitor if they are growing to prevent the risk of bleeding.

mTOR inhibitors

Following early successful trials, everolimus (an mTOR inhibitor) is now the first choice for preventing growing kidney tumours, unless they are bleeding.

However, as this is a relatively new treatment the long-term effects are not yet fully known.

Embolisation

mbolisation is designed to stop the blood supply to tumours.

During embolisation, the surgeon inserts a small tube known as a catheter into your groin at the top of your leg. They will use X-ray images to guide the catheter into the blood supply of your kidney.

A special substance is injected through the catheter to block the blood supply to the tumour. By blocking the blood supply, the tumour will become starved of oxygen and nutrients and shrink

Further kidney treatment

Very rarely, if you have a severe or total loss of kidney function, you may require: 


dialysis – where a machine is used to filter your blood  

a kidney transplant – where your failing kidney is replaced with a healthy one


Lung tumours

Women with multiple lung tumours who go on to develop lymphangioleiomyomatosis (LAM) will usually require medication. Until recently, some women were prescribed progesterone (a female sex hormone). However, this is no longer frequently used.

In more serious cases of LAM that lead to a collapsed lung, emergency surgery is required to repair the lung. In very severe cases, a lung transplant may be required.

Sirolimus

New trials have shown that a type of mTOR inhibitor called sirolimus can successfully halt the progression of LAM. After a year, women with LAM who had been taking sirolimus had reduced symptoms and an improved quality of life. 

However, after the women stopped taking sirolimus their lung function started to get worse again. The drug can also cause a number of side effects, such as feeling sick, constipation or diarrhoea.

Sirolimus is not yet licensed to treat LAM and more research is needed before it becomes an established treatment. However, the early results look promising. 

Eye tumours

Eye tumours rarely need any treatment because they do not usually grow big enough to impair your vision. In rare cases where vision is affected, a technique called photocoagulation can be used.

Photocoagulation is a type of laser surgery that uses lasers to burn away the blood vessels supplying the eye tumours with blood. Blocking the blood supply should shrink the tumours.

 

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Unlicensed medicines

If a medicine is unlicensed, it means the manufacturer of the medicine has not applied for a license for it to be used to treat that specific condition.

In other words, the medicine has not undergone clinical trials to see if it is effective and safe in the treatment of the condition.

Clinical trials are underway using mTOR inhibitors to treat certain types of tumours. Some experts think that mTOR inhibitors could soon be licensed to treat some of the tumours caused by the condition.

Complications of tuberous sclerosis 

Complications of tuberous sclerosis may develop if the condition gets worse. This is why regular screening and treatment is so important.

Possible complications include:


status epilepticus – a seizure that lasts for more than 30 minutes, or a series of repeated seizures where you do not regain consciousness in between

bronchopneumonia – having bronchitis (infection of the main airways of the lungs) at the same time as pneumonia (infection of the lung tissue)  

kidney failure – your kidney stops working completely


Status epilepticus and bronchopneumonia are the most common reasons for people with tuberous sclerosis dying early. They are more likely to occur in people with severe learning disabilities.  

SUDEP

If you have epilepsy that is difficult to treat, you may be at risk of sudden unexpected death in epilepsy (SUDEP). This is when somebody with epilepsy dies and no apparent cause can be found. SUDEP may affect about 1 in every 250 people with difficult epilepsy.

Find out more about SUDEP on the Epilepsy Action website.

Kidney problems

Kidney failure is usually caused by polycystic kidney disease, although sometimes it is related to multiple surgeries for bleeding angiomyolipomas (AMLs). AMLs are tumours in the kidneys that are made up of blood vessels, muscle and fat.

An individual tumour can grow larger than 3cm and keep growing. The tumour can then develop a huge but weak blood vessel, which may burst. This causes bleeding, which can be life threatening because of the size of the blood vessel. Over a lifetime, up to two to three out of 10 people with tuberous sclerosis will have an episode of bleeding.
 


Tuberous sclerosis