Tuberous Sclerosis Complex (TSC) Causes, Symptoms, Diagnosis, Treatment, Prevention

Tuberous Sclerosis Complex (TSC) Causes, Symptoms, Diagnosis, Treatment, Prevention


What is Tuberous sclerosis complex?


Tuberous sclerosis complex is a genetic disorder characterized by the growth of numerous noncancerous (benign) tumors in many parts of the body. These tumors can occur in the skin, brain, kidneys, and other organs, in some cases leading to significant health problems. Tuberous sclerosis complex also causes developmental problems, and the signs and symptoms of the condition vary from person to person.

Virtually all affected people have skin abnormalities, including patches of unusually light-colored skin, areas of raised and thickened skin, and growths under the nails. Tumors on the face called facial angiofibromas are also common beginning in childhood.

Tuberous sclerosis complex often affects the brain, causing seizures, behavioral problems such as hyperactivity and aggression, and intellectual disability or learning problems. Some affected children have the characteristic features of autism, a developmental disorder that affects communication and social interaction. Benign brain tumors can also develop in people with tuberous sclerosis complex; these tumors can cause serious or life-threatening complications.

Kidney tumors are common in people with tuberous sclerosis complex; these growths can cause severe problems with kidney function and may be life-threatening in some cases. Additionally, tumors can develop in the heart, lungs, and the light-sensitive tissue at the back of the eye (the retina).

Causes of Tuberous sclerosis complex


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 Tuberous Sclerosis Complex 1 and Tuberous Sclerosis Complex 2 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.

A range of skin rashes of tuberous sclerosis


The skin rashes of tuberous sclerosis can take a range of forms, including:
  • Ash leaf patch – patches of skin are white because they lack pigment. These patches tend to take the shape of a leaf and are sometimes present at birth, but usually fade over the years.
  • Shagreen patch – the skin patch has a textured, raised appearance, similar to orange peel. These patches are present at birth and usually form on the lower back. They can also develop later in life.
  • Facial angiofibroma – the affected person typically develops a rash across their nose and cheeks. At first, the rash appears like collections of red pin-points, then each mark develops into a small lump. When the child reaches their teenage years, little papules may also form around their finger and toenails.

Is Tuberous Sclerosis Complex inherited?


Although some individuals may inherit the disorder from a parent with Tuberous Sclerosis Complex, most cases occur as spontaneous mutations. In these situations, neither parent has the disorder or the faulty gene(s). Instead, a faulty gene first occurs in the affected individual.

In other cases, Tuberous Sclerosis Complex is an autosomal dominant disorder, which means that the disease is carried by a dominant gene. In those cases where it is passed from parent to child, only one parent needs to have the gene in order to produce the disease in a child. If a parent has the Tuberous Sclerosis Complex gene, each offspring has a 50 percent chance of developing the disorder. Children who inherit Tuberous Sclerosis Complex may not have the same symptoms as their parent and they may have either a milder or a more severe form of the disorder.

Some individuals acquire Tuberous Sclerosis Complex through a process called gonadal mosaicism. These patients have parents with no apparent defects in the two genes that cause the disorder. Yet these parents can have a child with Tuberous Sclerosis Complexbecause 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.

What are the signs and symptoms of Tuberous sclerosis complex (TSC)?


Tuberous Sclerosis Complex can affect any or all systems of the body, causing a variety of signs and symptoms. Signs of the disorder vary depending on which system and which organs are involved. The natural course of Tuberous Sclerosis Complex varies from individual to individual, with symptoms ranging from very mild to quite severe. In addition to the benign tumors that frequently occur in Tuberous Sclerosis Complex, other common symptoms include seizures, mental retardation, behavior problems, and skin abnormalities. Tumors can grow on any organ, but they most commonly occur on the brain, kidneys, heart, lungs, and skin. Malignant tumors are rare in Tuberous Sclerosis Complex. Those that do occur primarily affect the kidneys.

Kidney problems such as cysts and angiomyolipomas occur in an estimated 40 to 80 percent of individuals with Tuberous Sclerosis Complex, usually occurring between ages 20 and 30. Cysts are usually small, appear in limited numbers, and cause no serious problems. Approximately 2 percent of individuals with Tuberous Sclerosis Complexdevelop large numbers of cysts in a pattern similar to polycystic kidney disease during childhood. In these cases, kidney function is compromised and kidney failure occurs. In rare instances, the cysts may bleed, leading to blood loss and anemia.

Angiomyolipomas - benign growths consisting of fatty tissue and muscle cells-are the most common kidney lesions in Tuberous Sclerosis Complex. These growths, which are not rare or unique to Tuberous Sclerosis Complex, are found in about 1 in 300 people without Tuberous Sclerosis Complex. Angiomyolipomas caused by Tuberous Sclerosis Complex are usually found in both kidneys and in most cases they produce no 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 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 Tuberous Sclerosis Complex.

Three types of brain tumors are associated with Tuberous Sclerosis Complex: 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, which form in the walls of the ventricles-the fluid-filled cavities of the brain; and giant-cell astrocytomas, a type of tumor that can grow and block the flow of fluids within the brain, causing a buildup of fluid and pressure and leading to headaches and blurred vision.

Tumors called cardiac rhabdomyomas sometimes are found in the hearts of infants and young children with Tuberous Sclerosis Complex. 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 do not grow and probably will not affect the individual in later life.

Benign tumors called phakomas are sometimes found in the eyes of individuals with Tuberous Sclerosis Complex, 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.

A wide variety of skin abnormalities may occur in individuals with Tuberous Sclerosis Complex. Most cause no problems but are helpful in diagnosis. Some cases may cause disfigurement, necessitating treatment. The most common skin abnormalities include:

  • Hypomelanic 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.

  • Reddish spots or bumps called facial angiofibromas (also called adenoma sebaceum), which appear on the face (sometimes resembling acne) and consist of blood vessels and fibrous tissue.
  • Raised, discolored areas on the forehead called forehead plaques, which are common and unique to Tuberous Sclerosis Complex and may help doctors diagnose the disorder.
  • Areas of thick leathery, pebbly skin called shagreen patches, usually found on the lower back or nape of the neck.
  • Small fleshy tumors called ungual or subungual fibromas that grow around and under the toenails or fingernails and may need to be surgically removed if they enlarge or cause bleeding.
  • Other skin features that are not unique to individuals with Tuberous Sclerosis Complex, including molluscum fibrosum or skin tags, which typically occur across the back of the neck and shoulders, cafĂ© au lait spots or flat brown marks, and poliosis, a tuft or patch of white hair that may appear on the scalp or eyelids.
Tuberous Sclerosis Complex can cause seizures and varying degrees of mental disability. Seizures of all types may occur, including infantile spasms; tonic-clonic seizures (also known as grand mal seizures); or tonic, akinetic, atypical absence, myoclonic, complex partial, or generalized seizures.

Approximately one-half to two-thirds of individuals with Tuberous Sclerosis Complex have mental disabilities ranging from mild learning disabilities to severe mental retardation. Behavior problems, including aggression, sudden rage, attention deficit hyperactivity disorder, acting out, obsessive-compulsive disorder, and repetitive, destructive, or self-harming behavior, may occur in children with Tuberous Sclerosis Complex. Some individuals with Tuberous Sclerosis Complex may also have a developmental disorder called autism.

How is Tuberous sclerosis complex (TSC) diagnosed?


In most cases the first clue to recognizing Tuberous Sclerosis Complex is the presence of seizures or delayed development. In other cases, the first sign may be white patches on the skin (hypomelanotic macules).

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 the 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 dilated pupils. A Wood's lamp or ultraviolet light may be used to locate the hypomelantic macules which are sometimes hard to see on infants and individuals with pale or fair skin.

In infants Tuberous Sclerosis Complex may be suspected if the child has cardiac rhabdomyomas or seizures (infantile spasms) at birth. With a careful examination of the skin and brain, it may be possible to diagnose Tuberous Sclerosis Complex in a very young infant. However, most children are not diagnosed until later in life when their seizures begin and other symptoms such as facial angiofibromas appear.

Treatments and drugs for Tuberous sclerosis complex (TSC)


There's no cure for Tuberous Sclerosis Complex, but treatment can help manage specific signs and symptoms.

Medication


Anti-epileptic drugs may be prescribed to control seizures, and other medications may be prescribed to help manage behavior problems. A medication called everolimus (Afinitor, Zortress) is used to treat certain types of brain growths that can't be surgically removed in people with Tuberous Sclerosis Complex. Another medication that may prove helpful for brain growths and other problems caused by tuberous sclerosis is an immune-suppressing drug called sirolimus (Rapamune). The topical form of this drug may help treat the acne-like skin lesions that can occur in Tuberous Sclerosis Complex. However, sirolimus is still in clinical trials and considered experimental as a treatment for Tuberous Sclerosis Complex.

Educational therapy


Early intervention can help children overcome developmental delays and meet their full potential in the classroom.

Occupational therapy


Through occupational therapy, a person who has Tuberous Sclerosis Complex can improve his or her ability to handle daily tasks.

Psychological therapy


Talking with a mental health therapist may help you or your child accept and adjust to living with this disorder.

Surgery


If a lesion affects the ability of a specific organ — such as the kidney — to function, the lesion may be surgically removed. Sometimes surgery can help control seizures caused by brain lesions that don't respond to medication. Surgical procedures such as dermabrasion or laser treatment may improve the appearance of skin lesions.

Tuberous Sclerosis Complex is a lifelong condition that requires careful monitoring and follow-up. With appropriate treatment, however, many people who have Tuberous Sclerosis Complex lead full, productive lives and enjoy a normal life expectancy.

Prevention for Tuberous sclerosis complex

There is currently no known method of prevention against Tuberous Sclerosis Complex. Most cases occur randomly and are not inherited.

Prenatal DNA testing, such as amniocentesis or chorionic villus sampling, may be performed if there is a family history of Tuberous Sclerosis Complex. However, there are serious risks associated with prenatal testing, including miscarriage. Therefore, patients should discuss the potential health risks and benefits of prenatal genetic testing before making any health-related decisions.

People with family histories of Tuberous Sclerosis Complex can meet with genetic counselors. These professionals can help patients understand the risks of having a child with Tuberous Sclerosis Complex. A genetic counselor can also explain the different types of genetic tests, including their potential risks and benefits. These counselors can also help patients understand the results and implications of genetic tests.

What is the prognosis of Tuberous sclerosis complex?


The prognosis for individuals with Tuberous Sclerosis Complex is highly variable and depends on the severity of symptoms.  Tthose individuals with mild symptoms usually do well and have a normal life expectancy, while paying attention to Tuberous Sclerosis Complex-specific issues.   Individuals who are severely affected can suffer from severe mental retardation and persistent epilepsy. 

All individuals with Tuberous Sclerosis Complex are at risk for life-threatening conditions related to the brain tumors, kidney lesions, or LAM.  Continued monitoring by a physician experienced with Tuberous Sclerosis Complex is important.  With appropriate medical care, most individuals with the disorder can look forward to normal life expectancy.

What research is being done for Tuberous sclerosis complex?


Within the Federal Government, the leading supporter of research on Tuberous Sclerosis Complex is the National Institute of Neurological Disorders and Stroke (NINDS). The NINDS, part of the National Institutes of Health (NIH), is responsible for supporting and conducting research on the brain and the central nervous system. NINDS conducts research in its laboratories at NIH and also supports studies through grants to major medical institutions across the country. The National Heart, Lung, and Blood Institute and the National Cancer Institute, also components of the NIH, support and conduct research on Tuberous Sclerosis Complex.

Scientists who study Tuberous Sclerosis Complex seek to increase our understanding of the disorder by learning more about the Tuberous Sclerosis Complex 1 and Tuberous Sclerosis Complex 2 genes that can cause the disorder and the function of the proteins-tuberin and hamartin-produced by these genes. Scientists hope knowledge gained from their current research will improve the genetic test for Tuberous Sclerosis Complex and lead to new avenues of treatment, methods of prevention, and, ultimately, a cure for this disorder.

Research studies run the gamut from very basic scientific investigation to clinical translational research. For example, some investigators are trying to identify all the protein components that are in the same 'signaling pathway' in which the Tuberous Sclerosis Complex 1 and Tuberous Sclerosis Complex 2 protein products and the mTOR protein are involved. Other studies are focused on understanding in detail how the disease develops, both in animal models and in patients, to better define new ways of controlling or preventing the development of the disease. Finally, clinical trials of rapamycin are underway (with NINDS and NCI support) to rigorously test the potential benefit of this compound for some of the tumors that are problematic in Tuberous Sclerosis Complex patients.