What is TSC ?
Tuberous sclerosis complex (TSC) is a genetic disorder that causes tumors to form in many different organs, primarily in the brain, eyes, heart, kidney, skin and lungs. The aspects of TSC that most strongly impact quality of life are generally associated with the brain: seizures, developmental delay, intellectual disability and autism.
Genetics of TSC
Genes are the biochemical instructions found inside the cell, not unlike the programs found inside computers. Human beings have 22 pairs of chromosomes, as well as a pair of sex chromosomes. Females have two X chromosomes and males have an X and a Y chromosome. Our genes come in pairs, with one copy inherited from the mother and the other from the father. All people have variations in their genes – some of which cause diseases and others increase risk for developing some diseases, and some variations cause no problems at all. Some of these variations have been passed down from one parent, and some variations are unique to individual human beings.
TSC is caused by a change or variation (called a mutation when it causes disease) in either the TSC1 gene on chromosome 9 or the TSC2 gene on chromosome 16. TSC is an autosomal dominant genetic disorder. This means an individual with TSC has a mutation in one copy of either of the TSC genes that then causes the disease. Many genetic disorders such as TSC can be sporadic, meaning the disorder has not previously occurred in that family. Such sporadic occurrences are the result of a new genetic mutation and account for approximately two-thirds of all cases of TSC. The remaining one-third of cases are the result of a TSC gene containing a mutation being passed along (inherited) from either the mother or the father to their child.
Signs and Symptoms
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. Although these changes can be called tumours, they are not cancerous
TSC can cause the following changes in the brain:
Cortical and subcortical tubers The cortical tuber (from which TSC was originally named) is a disorganized area of the brain that contains abnormal cells. Some individuals with TSC have numerous tubers, whereas others will not have any. It is thought that tubers develop along with the rest of the brain, so that the number of tubers in the brain of most individuals with TSC stays approximately the same throughout their life. This also means that tubers can be seen as early as 20 weeks’ gestation on a fetal MRI. Tubers and/or the brain area surrounding a tuber play a role in the development of seizures in individuals with TSC.
Subpendymal nodules (SENs) SENs are small accumulations of cells that are located on the walls of the cerebral ventricles (the spaces in the brain that contain cerebrospinal fluid (CSF). The nodules often accumulate calcium, and are then easily identified on MRI imaging of the brain. SENS are usually less than 1cm in diameter.
Subpendymal giant cell astrocytomas (SEGAs) SEGA is a type of brain tumor that occurs in individuals with TSC that is noncancerous and is not malignant but can still be very problematic.SEGAs can be problematic because they may grow sufficiently large to block the flow of CSF within the brain, causing an increase in the pressure within the head and enlargement of the fluid-filled ventricles (a process known as hydrocephalus). This build up of pressure can result in symptoms such as vomiting, nausea, headache and changes in appetite, behavior and mood.
Doctors: Neurologists, Neurosurgeon
Most people with tuberous sclerosis complex (TSC) have changes in their skin. There may be light colored spots, called hypomelanotic macules, and bumps on the skin of several different types (angiofibromas, cephalic fibrous plaques, shagreen patches, and ungual fibromas). In combination, these skin features are found only in TSC, and they are often used to diagnose TSC, especially in young patients.
Nearly 50% of individuals with TSC have eye involvement. This may be higher as many individuals with TSC do not receive a good eye exam that would reveal either hamartomas or depigmented areas of the retina.
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 particular renal disorders in TSC: renal cysts, renal angiomyolipoma and renal cell carcinoma.
Lung involvement in tuberous sclerosis complex (TSC) has been recognized for many years.Two forms of lung involvement in TSC have been described:
Lymphangioleiomyomatosis (LAM)/pulmonary cysts Lymphangioleiomyomatosis (LAM) is a lung disease that affects women more often than men, usually between the onset of puberty and menopause. LAM is characterized by an unusual type of muscle cell that invades the lungs, airways, and blood and lymph vessels. The source of the cells that invade the lung is not clear, although the uterus and angiomyolipomas are possible candidates. Over time, these muscle cells destroy the lungs and make it difficult for oxygen to get across the wall of the airway and into the blood cells. This prevents the lungs from providing oxygen to the rest of the body.- Multifocal micronodular pneumocyte hyperplasia (MMPH) Multifocal micronodular pneumocyte hyperplasia (MMPH) consists of overgrowth (hyperplasia) of the pneumocytes (a specific type of cell found in the lining of the air sacs in the lung) into small nodules. An individual with TSC who has MMPH may have a few or many nodules in their lungs. This condition occurs with equal frequency in men and women with TSC and does not usually produce clinical symptoms.
The primary cardiac finding in patients with the tuberous sclerosis complex (TSC) is the presence of rhabdomyomas. These are non-malignant (or non-cancerous) tumors that can occur anywhere in the heart, but most commonly occur in the ventricular and septal walls. Approximately 50% of patients with TSC have cardiac rhabdomyomas, and 50% of patients with cardiac rhabdomyomas have TSC. The presence of multiple, rather than single, tumors is more consistent with a diagnosis of TSC. Sporadic vascular abnormalities can occur in TSC. Teeth Oral/dental health is a critical part of maintaining overall health in TSC. The teeth and gums in TSC individuals are slightly different and often take a little more care to keep healthy.
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.
Assessment and management of these signs of TSC can involve a number of different professionals:
- A psychiatrist is a medical doctor who specialises in the treatment of mental illness. Some psychiatrists will specialize in treating younger people, so may be called child and adolescent psychiatrists.
- A neuropsychiatrist is a medical doctor who specialises in the links between the brain and behaviour. They will usually be a psychiatrist before they take additional training to be a neuropsychiatrist.
- A developmental paediatrician is a medical doctor who has a special interest, training and experience in the development of children. This includes how they acquire knowledge and skills, and how they learn to behave and socialize. Developmental paediatricians tend to specialise in disorders of development such as autism, ADHD and intellectual disability.
- A clinical psychologist is a specially qualified psychologist who can provide assessment as well as treatment.
- Counsellors, social workers and therapists can have a range of different qualifications and experience.
- Special education teachers are specially trained to work with children who have special needs. They may be involved in creating individual plans, adapting teaching methods and equipment to suit the needs of the individual student.
Different professionals will describe different aspects of behaviour, learning and mental health differently. This can be confusing and people with TSC and their carers should ask for clarification if they are unsure what aspect of behavior, learning or mental health is being assessed or treated.
The specific tests that are performed depend on the age of the individual who is suspected of having TSC and may include the following:
– MRI (magnetic resonance imaging) scan of the brain
– CT (computed tomography) scan of the lungs liver and kidneys
– Ultrasound scan of the kidneys
– Echocardiogram (ECG) ultrasound to examine the structures of the heart
– Eye examination to look for abnormalities of the retina
– Skin examination under ultraviolet light
– Genetic testing to diagnose and/or confirm a diagnosis of TSC
Genetic Testing of TSC
Genetic testing allows individuals with TSC, family members and healthcare providers to know exactly what mutation in either the TSC1 or TSC2 gene caused TSC. This information may be helpful for a number of reasons. In some cases, the identification of a TSC1 or TSC2 mutation will facilitate a definite genetic diagnosis of TSC in an individual who has not yet developed enough symptoms for a clinical diagnosis. In approximately 15% of individuals with TSC, no mutation is identified in either TSC1 or TSC2. While a negative DNA test result cannot rule out a diagnosis of TSC, a positive result confirms the diagnosis. In other cases, an individual may have a definite diagnosis of TSC, and family members may wish to know their own genetic status without undergoing extensive clinical evaluations. Upon identifying the TSC mutation in the individual with a definite diagnosis of TSC, any other family member can be easily tested to determine whether he or she is also affected. In addition, the availability of DNA mutation results makes reproductive decision-making possible.
How is TSC Diagnosed?
|MAJOR FEATURES||MINOR FEATURES|
|1. Hypomelanotic macules (≥3. at least 5·mm diameter)||1. “Confetti” skin lesions|
|2. Angiofibromas (≥3) or fibrous cephalic plaque||2. Dental enamel pits (>3)|
|3. Ungual fibromas (≥2)||3. Intraorallibromas (≥2)|
|4. Shagreen patch||4. Retinal achromatic patch|
|5. Multiple retinal hamartomas||5. Multiple renal cysts|
|6. Cortical dysplasias*||6. Nonrenal hamartomas|
|7. Subependymal nodules|
|8. Subependymal giant cell astrocytoma|
|9. Cardiac rhabdomyoma|
|10. Lymphangioleiomyomatosis (LAM)**|
|11. Angiomyolipomas (>2)**|
Definite diagnosis: Two major features or one major feature with ≥ 2 minor features.
Possible diagnosis: Either one major feature or ≥2 minor features.
* Includes tubers and cerebral white matter radial migration lines.
**A combination of the two major Clinical features (LAM and angiomyolipomas) without other features does not meet criteria for a definite diagnosis.