Tuberous Sclerosis Complex (TSC) is a genetic disorder that affects people in many different ways. Some people with TSC are so mildly affected they may go through life without the diagnosis being made.

TSC is often referred to simply as Tuberous Sclerosis (TS) and affects approximately 1 in 9000 people. There is no cure for TSC but there are treatments available for many of the symptoms.

The common features that are characteristic of TSC are:

  • Brain: Many different types of non-cancerous growths (tumours or lesions) may occur in the brain. About 50% of people with TSC have an IQ in the normal range. Individuals with TSC can have clinical features such as epilepsy (seizures), learning disabilities, intellectual impairment, autism spectrum disorders and sleep disorders. There is a wide range of severity of these symptoms.
  • Skin: Multiple white patches (hypopigmented macules) on the skin are often the first sign of TSC. Other skin rashes may develop with time, but none of these skin symptoms cause serious medical problems.
  • Heart: Rhabdomyomas are growths that occur in the heart muscle. These often do not cause any medical problems and generally shrink with age. Very occasionally, surgery is required if the growth is blocking blood flow.
  • Kidneys: Cysts and growths can occur in the kidneys. The most common type of kidney (renal) growth is called an angiomyolipoma or AML. These can sometimes cause kidney problems and there is a slightly increased risk of kidney cancer in people with TSC. A very small number of people also have another renal problem, called polycystic kidney disease as well as TSC.
  • Lungs: Cysts can occur in the lungs. This is called lymphangioleiomyomatosis (LAM) of the lung. LAM may not cause any problems or may cause shortness of breath requiring medical attention. LAM affects about 30% of women with TSC, and is seen only very rarely in men.
  • Eyes: Benign tumours called harmatomas can occur at the back of the eye (retina). These generally do not affect vision.

There is no cure for TSC, but the symptoms can be treated or managed. Regular surveillance to look for symptoms and early treatment are associated with better health and quality of life for people with TSC.

The genetic changes that cause Tuberous Sclerosis can lead to signs of TSC in many different organs of the body.

Signs and symptoms of tuberous sclerosis

This section proviudes in-depth information about the different signs and symptoms of TSC. This information should not be used as a substitute for medical advice. Readers are warned not to take any action without first seeking medical advice.

  • Skin
  • Brain
  • Epilepsy
  • Behavioural, intellectual, learning and psychiatric challenges
  • Kidneys
  • Heart
  • Lungs
  • Eyes

Skin

Nearly all people with Tuberous Sclerosis will have at least one of the signs of TSC on their skin. For many people these are one of the first signs of TSC. Signs of TSC on the skin are important for diagnosis of TSC as they comprise many of the minor and major features in the diagnostic criteria (link).

Although the signs of TSC on the skin are benign (non-cancerous) they can be a major concern for individuals with TSC and impact on self-esteem and social interactions.

A term used by health professionals for things to do with the skin is ‘dermatology’ and skin doctors are called dermatologists. Some treatments for the TSC skin signs can also be performed by a cosmetic surgeon.

Some TSC skin signs appear at birth, others develop later in childhood or even adulthood. Currently there is no way to predict how many TSC skin signs will develop during childhood, but they tend to remain stable during adulthood.

The skin signs of TSC are highly variable from one individual with TSC to the next, even within the same family. Some people have TSC skin signs that are hardly noticeable. Others may have larger TSC skin signs that cause pain or bleed easily.

The different signs of TSC on the skin are:

  • Hypomelanotic macules (White spots)
  • Facial Angiofibromas
  • Fibrous Plaques
  • Shagreen Patch
  • Nail Lesions
  • Other skin signs

Brain

Almost all people with TSC have some signs of TSC in their brain. These signs may cause only mild symptoms in some people and severe symptoms in others.

A term used by health professionals for things to do with the brain is neurology. Doctors who specialize in the brain are called neurologists. Epileptologists are a special kind of neurologist who specialises in treating Epilepsy. A neurosurgeon may be involved to determine if brain surgery is a possible treatment for an individual with TSC.

TSC can cause the following changes in the brain:

  • Cortical and subcortical tubers
  • Subpendymal nodules (SENs)
  • Subpendymal giant cell astrocytomas (SEGAs)

Although these changes can be called tumours, they are not cancerous.

The following topics are covered separately:

  • Epilepsy
  • Behavioural, intellectual, learning and psychiatric challenges
  • Cortical and subcortical tubers
  • Subpendymal nodules (SENs)
  • Subpendymal giant cell astrocytomas (SEGAs)

Epilepsy

Epilepsy is a neurological condition that makes people susceptible to seizures. A seizure is a change in sensation, awareness or behaviour brought about by a brief electrical disturbance in the brain. Seizures are sometimes also called convulsions or fits. Another word for epilepsy is a seizure disorder.

Approximately 75% – 90% of individuals with TSC will have Epilepsy at some point in their life. Epilepsy can start at any age but many babies with TSC have a seizure during the first year of life.

A term used by health professionals for things to do with the brain is neurology. Doctors who specialize in the brain are called neurologists. Epileptologists are a special kind of neurologist who specialises in treating Epilepsy. An epilepsy nurse may also assist with epilepsy treatment and education

A neurosurgeon may be involved to determine if brain surgery is a possible treatment for an individual with TSC.

Epilepsy occurs in TSC is because the areas of abnormal brain development contain abnormal nerve cells. These nerve cells have abnormal bursts of electrical activity which cause the seizures.

Researchers are not sure which changes in the brain lead to seizures and why. The number and size of cortical tubers is thought to play a big part. The exact gene change that has caused TSC in the individual may also play a part. Because this is unknown, it is not possible to predict whether an individual with TSC will have seizures, what type they will be and how they should be treated.

Types of seizures may also change throughout the life of someone with TSC and epilepsy.

The different changes that occur in the brain due to TSC are covered on a separate page. Impacts of TSC and epilepsy on learning, behaviour and mental health is covered on a separate page.

  • Focal, partial, generalised – what is the difference?
  • Infantile spasms
  • Other types of seizures
  • Epilepsy syndromes
  • The link between seizures and developmental delay
  • Status epilepticus

Behavioural, Intellectual, Learning and Psychiatric challenges

The impacts of TSC on behavior, learning and mental health are often the most difficult symptoms of TSC for families to cope with. It is important that families, carers, educators and health professionals are aware of these challenges; look for them in the TSC affected person at regular intervals; and implement appropriate strategies to deal with them.

The aim of understanding the different areas where a person with TSC may have difficulties is to identify the areas of strength and weakness in each individual. This is done through regular assessment and testing. After these strengths and weaknesses are identified the team of professionals can work with the family to work out what additional help may be needed to help the individual achieve their potential.

Kidneys

Most people with TSC will develop some signs of TSC in their kidneys during their lifetime. However, with proper surveillance and care, most people with TSC will not have major problems with their kidneys.

Doctors who specialize in kidneys are called nephrologists. Another term used by health professionals for things to do with the kidneys is ‘renal’ and kidney doctors are also called renal physicians. Surgeons who operate on kidneys are called urologists.

Kidneys can be affected by TSC in a number of ways:

Heart

At birth or in infancy, approximately 50% of individuals with TSC have at least one tumour in their heart. These benign (non-cancerous) tumours are called a cardiac rhabdomyoma do not usually cause any symptoms. Most rhabdomyomas decrease in size or disappear within the first 1-2 years of life.

The term used by health professionals for things to do with the heart is cardiac. Doctors who specialise in children’s hearts are called paediatric cardiologists.

Lungs

Some people with TSC, especially women, may have signs of TSC in their lungs. The most common sign is lymphangioleiomyomatosis (LAM). Most of these people will not have any symptoms but it is still recommended for all women to have a scan of their chest to look for signs of TSC in their lungs.

Terms used by health professionals for things to do with the lungs are respiratory and pulmonary. Doctors who specialize in lungs and lung disease can be called respiratory physicians.

Signs of TSC in the lungs are much more commonly found in women, usually only in adulthood. There have only been a small number of cases of TSC affecting the lungs in men.

The lungs can be affected by TSC in two different ways:

People with TSC can be affected with many other lung diseases, just like everyone else in the community. These include infections such as influenza and pneumonia as well as asthma.

Eyes

There are a variety of signs of TSC that can involve the eyes and approximately 50% of people with TSC have some signs of TSC in their eyes. Loss of vision is not common in TSC.

Terms used by health professionals for things to do with the eyes are ophthalmic and ocular. An ophthalmologist is a medical doctor who specializes in the eyes. The retina is the part of the eye that transmits what is seen by the eye to the brain via the optic nerve.

There are many different signs of TSC that can occur in and around the eyes. Many of these do not cause major problems but can be helpful when trying to diagnose TSC.

Even for a doctor, it can be very difficult to tell if an abnormality in the eyes is caused by TSC or some other cause.

  • Behavioural difficulties
  • Developmental delay
  • Autism Spectrum Disorders
  • Attention Deficit Hyperactivity Disorder (ADHD)
  • Mood and Anxiety Disorders
  • Other Psychiatric Disorders
  • Sleep difficulties
  • Intellectual ability, learning and academic skills
  • What causes these symptoms of TSC?
    • Kidney Cysts and Polycystic Kidney Disease
    • Angiomyolipomas (AMLs)
    • Kidney Cancer
    • Impaired kidney function
    • Rhabdomyoma
    • Symptoms
    • Other
    • Lymphangioleiomyomatosis (LAM)
    • Multifocal micronodular pneumocyte hyperplasia (MMPH)
    • Retinal Harmatomas
    • Retinal Hypopigmented Lesions
    • Angiofibromas around the eyes
    • Vision problems caused by intellectual impairment
    • Vision problems caused by epilepsy treatment
    • Other signs

Genetic testing for tuberous sclerosis

Clinical geneticists are medical doctors that specialise in genetics and genetic diseases. Genetic counsellors are health professionals that are trained in both counselling and medical genetics. Genetic couselling is a process that can help the whole family understand how TSC is inhetited and to make decisions about management and reproduction.

Important points

What causes Tuberous Sclerosis Complex (TSC)?

Genes, chromosomes and genetic conditions

In all the cells of our body, our genes are found on chromosomes (long strings of genes). Most of our chromosomes (and therefore our genes) come in pairs – one of each copy from each parent. The only exception is the sex chromosomes, which determine whether we are male or female. We have many thousands of genes that provide information for our body to grow, develop and remain healthy. The gene sends messages to the cell to make important chemical products such as proteins.

Everyone has variations in the information in their genes, which is why we are all unique. Variations can either be harmless or at times, can cause a gene to be faulty. Variations that make a gene faulty are called mutations. The information contained in the faulty gene, and its product, is impaired (see Genetics Fact Sheet 4 & Fact Sheet 5).

Faulty genes do not work as they should in the body and are unable to provide the correct information to our cells. A fault in either of two different genes – one called TSC1 and one called TSC2 – can cause TSC. These genes make proteins that make sure cells only grow as fast as they need to. If these proteins are not being produced correctly, some cells grow in an uncontrolled way forming the tumours seen in people with TSC.

What is the pattern of inheritance in TSC families?

A faulty TSC gene can either be passed down (inherited) from a parent or may occur as a new faulty gene just before or after conception. Once a faulty gene is present in an individual’s egg or sperm cells, it can be passed on to future generations. This is referred to as genetic inheritance.

Two factors influence the pattern of inheritance of a faulty TSC gene.

The pattern of inheritance in families of the faulty gene causing TSC is therefore described as autosomal dominant inheritance (see Genetics Fact Sheet 9).

When a parent has TSC

In about 30% of the cases, TSC is inherited from an affected parent. When one of the parents has TSC due to the faulty TSC gene, there are four possible combinations of the genetic information that can be passed on to their children. This means that, in each pregnancy:

While the picture shows the father as the parent with the faulty TSC gene copy, the same situation would arise if the mother had the faulty TSC gene copy. TSC usually affects men and women equally.

Autosomal dominant inheritance

Figure 1: Autosomal dominant inheritance when one parent has a faulty copy of one TSC gene. The faulty TSC gene copy is represented by ‘D’; the working copy by ‘d’

When neither parent has TSC but they have a child with the condition

In approximately 70% of cases, the person with TSC is the first in the family with the condition. In these people, the condition resulted from a change that occurred in one copy of the TSC1 or TSC2 genes during formation of the egg or sperm, during conception or shortly after. These changes that make one of the TSC gene copies faulty are called ‘spontaneous mutations’. Spontaneous mutations are not caused by any action of the parents but arise by chance, as a new change.

Once a person has TSC s/he may potentially pass on the faulty gene copy to his/her children as described earlier.

If the TSC gene became faulty shortly after conception, not all of the baby’s cells may contain the gene variation; this individual is said to be ‘mosaic’ for the faulty TSC gene. They may experience milder symptoms because the faulty gene may not be present in all of the organs usually affected in TSC. The faulty gene might not be in all the egg or sperm cells of an individual with mosaic TSC. Their chance of passing on the faulty gene is therefore less than 50% (see Genetics Fact Sheet 13).

If a child of a parent who is mosaic for TSC inherits the faulty TSC gene copy, they may be more severely affected by TSC than their parent. This is because the child has the faulty gene in all the cells of their body, while their parent only has the faulty gene in some cells. That child also has a 50% risk of passing on the faulty gene copy to his or her children.

Because of the possibility that an unaffected parent of a child with TSC is mosaic for the faulty TSC gene, the chance of having another child affected by TSC is estimated between 1% and 2%. The chance that a spontaneous mutation in the TSC gene would happen again in further pregnancies is low.

TSC does not ‘skip generations’. However sometimes the features of the condition are so subtle that individuals do not realise they have TSC. An assessment by a skin specialist (dermatologist), eye doctor (ophthalmologist) and genetics doctor (clinical geneticist) may be useful in either confirming or ruling out that someone is affected with TSC.

Can a person have a test for a faulty TSC gene?

Even though TSC is a genetic condition, genetic testing is not needed to diagnose the condition. Most people with TSC will have enough physical signs of the condition for a specialist to diagnose them with confidence.

Genetic testing is available but is complex, time consuming and expensive. Testing the TSC1 and TSC2 genes will find a mutation in only about 80% of affected individuals. This is because there may be other genes that cause TSC that have not yet been identified. Alternatively, it is also possible that current genetic testing techniques are not yet sensitive enough to pick up all the variations that can cause TSC.

Genetic testing can however be helpful in some situations such as:

  • Confirming a possible diagnosis of TSC where there aren’t enough clinical features for a specialist to make a confident diagnosis.
  • Testing a baby in pregnancy (prenatal testing) or an embryo in IVF (pre-implantation genetic diagnosis) for TSC where one of the parents is affected (see Genetics Fact Sheet 17C & Fact Sheet 18)
  • Testing parents, sisters or brothers of someone with TSC to establish whether or not they have TSC

Genetic testing may also be helpful in the future as new treatments for TSC may be specific to either the TSC1 or TSC2 gene.

It is highly recommended that testing be discussed in the context of genetic counselling (see Genetics Fact Sheet 3).

Prepared by: A/Prof Kristine Barlow-Stewart & Ron Fleischer, The Centre for Genetics Education; Clare Stuart, The Australasian Tuberous Sclerosis Society. This page has been adapted from the Genetics Fact Sheet that has been co-authored by The Australasian Tuberous Sclerosis Society and The Centre for Genetics Education.

Last Reviewed: 21/01/2013

Reproduced with kind permission from the Australasian Tuberous Sclerosis Society.