Tuberous sclerosis (TS) is a hereditary neurological condition that affects all ages. The name arises from the potato stem-shaped growths that occur in the brain, also known as tubers. These growths often involve overgrowth of nerves or the connective tissue within them, which is described by the term sclerosis.
TS is also known by the names tuberous sclerosis complex and Bourneville's disease. Neurological symptoms may include tubers and other non-cancerous growths in the brain, cancerous brain tumors, seizures , and mental retardation or developmental delay.
Nearly everyone with TS has some symptoms affecting their skin. These include light-colored patches called ash-leaf spots, acne-type growths on the face, nail beds, and the body, and shagreen patches. Other common symptoms of TS are kidney cysts, kidney growths, and heart tumors that may develop at a very young age or even before birth.
According to the National Institute of Neurological Disorders and Stroke (NINDS), TS affects about 1 in 6,000 newborns. As many as 25,000 to 45,000 people in the United States and 1-2 million people worldwide have the disorder. Its true incidence may be higher because mildly affected individuals may not come to medical attention. TS has been reported in all ethnic groups and races with equal frequency.
Two genes for TS have been identified, and males and females are equally affected with the condition. About one third of people with TS have an affected parent as well.
Causes and symptoms
Always known to be hereditary, mutations in two different genes are now known to cause TS. These genes are TSC1 and TSC2, and were discovered in 1993 and 1997 on chromosomes 16 and 9 respectively. TS is inherited in an autosomal dominant manner, meaning that an affected individual has a 50/50 chance to pass a disease-causing mutation to his or her children, regardless of their gender. As a result, strong family histories of TS are common.
TSC1 and TSC2 normally code for specific proteins, hamartin and tuberin, which are felt to be necessary for neurological functioning. Reduced amounts of these proteins in the brains of people with TS may contribute to the neurological complications associated with the condition.
The most common neurological symptoms in TS include seizures, learning and behavioral problems, and hydrocephalus . Seizures affect about 85% of people at some point in their lives. They can begin in very early childhood as infantile spasms , sometimes with hypsarrhythmia. The presence of these spasms at an early age often means more significant learning problems and more significant epilepsy later on.
Learning problems are not a certainty with TS; about 50% of people with the condition are known to have developmental delay or mental retardation. People with TS have an increased chance to develop certain behavioral disorders. Autism is seen in about 25–50% of people with TS, and this is felt to have a major influence on an individual's daily functioning. Parents of children with TS often raise concerns about autism or autistic-type characteristics, because this has a significant impact on routine activities like attending school. Though scientific studies
have been done to find exact neurological causes for autism in TS, none has provided consistent results.
A unique brain finding in TS is the cortical tuber, which is seen in about 90% of people with the condition. The number and size of tubers in a person can correlate with the degree of learning problems and seizures they may experience. Other brain findings in TS include subependymal hamartomas. Some of these may grow in childhood and block the normal flow of spinal fluid, causing hydrocephalus. Brain tumors like subependymal giant cell astrocytomas are a cause of health complications and death in TS.
Since skin changes are so common in TS, they can be some of the first signs of the condition that are noticed. Ash-leaf spots are the most common skin finding, followed by facial angiofibromas. These angiofibromas may cause slight disfigurement, but more often are a cosmetic concern. Darkened skin patches called cafe-au-lait spots may also occur, along with skin tags. Fortunately, none of the skin symptoms usually cause serious medical complications.
Kidney disease can be a serious medical concern in TS; it is the most frequent cause of death in people with TS older than 30 years. The most common renal finding is the angiomyolipoma, which is more commonly found in women at a younger age. Though these growths are non-cancerous, they can enlarge and disturb normal kidney function. Kidney cysts may occur, again more commonly in younger women. These cysts may be numerous and similarly disrupt normal kidney function as a result. Renal cell carcinoma can be a further symptom of TS, and kidney transplants may be necessary for any significant renal complication.
Cardiac rhabdomyomas are typically seen in early childhood, but occasionally may even be seen on a prenatal ultrasound. Most rhabdomyomas disappear with age, remaining stable and causing no symptoms; others may cause heart rhythm problems. Vascular disease may also be a part of TS, with some people having aneurysms of the abdomen and other areas of the body.
Lung problems are a part of TS, and affect women more often. Lymphangioleimyomas of the lung are common and affect about 1-4% of people with TS by interfering with normal lung function. Hormones may be a factor because pregnancy, menstruation, and estrogen have been associated with a worsening of these symptoms in some women. Interestingly, pulmonary problems have been associated with a milder case of TS, often with fewer learning problems and seizures.
Other symptoms of TS include growths on the retinas called hamartomas, which are not usually problematic. There have been no typical ages in which eye involvement occurs in TS.
Up until the discovery of TSC1 and TSC2, the diagnosis of TS was made on a clinical basis. Criteria for clinical diagnosis were updated in 1998 at the Tuberous Sclerosis Complex Consensus Conference.
Revised diagnostic criteria for tuberous sclerosis complex (TSC)
The major features include:
- facial angiofibromas or forehead plaque
- non-traumatic ungual or periungual fibroma
- hypomelanotic macules (more than three)
- shagreen patch
- multiple retinal nodular hamartomas
- cortical tuber
- subependymal nodule
- subependymal giant cell astrocytoma
- cardiac rhabdomyoma, single or multiple
- renal angiomyolipoma
The minor features include:
- multiple randomly distributed pits in dental enamel
- hamartomatous rectal polyps
- bone cysts
- cerebral white matter radial migration lines
- gingival fibromas
- non-renal hamartoma
- retinal achromic patch
- "confetti" skin lesions
- multiple renal cysts
Definite TSC: Either two major features, or one major feature plus two minor features. Probable TSC: One major plus one minor feature. Possible TSC: Either one major feature, or two or more minor features.
Most brain findings in TS can be identified with magnetic resonance imaging (MRI) or computed tomography (CT ) scans. Seizures can be documented from electroencephalogram (EEG) monitoring. Skin changes are often found by using a Woods lamp, which makes them more obvious during a physical examination. Routine ultrasounds of the kidney often find and help monitor cysts and angiomylipomas. Cardiac involvement may be seen as early as a prenatal ultrasound, or with an echocardiogram in early life. Electrocardiograms may be necessary to help detect heart rhythm problems. For women in particular, a CT scan of the chest is important to detect lung lymphangiomyomatosis. For all, an ophthalmology examination is important to detect retinal involvement.
Genetic testing is available for TS via gene sequencing. It is useful for confirming a clinical diagnosis, prenatal diagnosis, or family testing when there is an identified TSC mutation in the family. Sequencing of the TSC1 and TSC2 genes is not perfect; it detects about 80% of people with TS. An informative test result is one that identifies a known mutation in either gene, and this confirms that the person has TS. A negative test result does not identify a mutation in either gene. This either means that the tested individual does not have TS, or has a mutation that cannot be found through testing and truly has the diagnosis.
Treatment for people with TS is usually very specific to the person, since symptoms vary greatly. The typical treatment team for someone with TS may include a neurologist , neurosurgeon, medical geneticist, genetic counselor, dermatologist, cardiologist, pulmonologist, nephrologist, ophthalmologist, social worker, and a primary care provider. Often times there are pediatric specialists in these fields who aid in the care for children. Care providers in pediatric development are particularly important, such as speech-language therapists and pediatric neuropsychologists.
There is no cure for tuberous sclerosis. Therefore, treatment is based upon symptoms.
Seizures may be treated with various anti-epilepsy medications. Those with significant seizures may be tried on a ketogenic diet, which consists of frequent meals of high-fat foods. While challenging, the ketogenic diet yields good results in some cases.
Learning or behavioral problems are often serious issues, but awareness and developmental interventions often help families with TS. Pediatricians who have an interest in child development are a good resource, particularly if a child with TS is showing signs of autism.
Hydrocephalus can be serious and even lead to learning problems if left untreated, so surgery to drain accumulated fluid in the brain may be necessary. While most growths in the brain are non-cancerous, brain tumors are typically treated as they would be in someone without TS.
Since most skin complications of TS cause no medical problems, treatment is not often necessary. Some angiofibromas, particularly on the face, may be problematic and require removal. Laser treatments may also be effective to reduce the appearance of some skin changes.
Many kidney growths cause no health problem in TS, but some individuals may have kidney cysts similar to those found in polycystic kidney disease (Type 1). In these cases, kidney function may be disturbed and the person might need a kidney transplant after some time. Those with renal cell carcinoma would be treated as anyone with this complication.
Most rhabdomyomas cause no problems, but some may need surgery to keep their hearts working well. Surgery may also be required for someone with a severe heart rhythm problem.
People with lung function problems may need to be treated with medications, hormone therapy, or surgery if necessary.
Visual complaints are not as common for people with TS, since retinal growths do not usually cause symptoms. In rarer cases, vision may be disturbed and treated like someone without TS.
As of early 2004, there were two clinical studies recruiting subjects in the United States. Both were at the National Heart, Lung, and Blood Institute (NHLBI) at the National Institutes of Health in Bethesda, Maryland. One study was studying skin tumors in people with TS, and the other was studying disease progression in people with TS who have lymphangioleimyomatosis. More information about these trials can be found at www.clinicaltrials.gov.
Prognosis for someone with tuberous sclerosis is highly dependent upon symptoms they experience. Those who die may do so as a result of significant neurological, pulmonary or cardiac complications. People with TS often have routine medical appointments dealing with symptoms as they arise.
Many people with TS survive into adulthood, and studies are attempting to learn more about long-term prognosis as people with TS age. It is challenging to gain this information because older people with milder forms of TS may not present for medical care frequently, or may not even know they have the condition.
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Deepti Babu, MS, CGC
Tuberous sclerosis is a genetic disorder in which noncancerous (benign) tumors grow on the brain, skin, kidneys, eyes, heart, and lungs.
The name tuberous sclerosis refers to characteristics of the benign tumors that grow within the brain. The tumors have root-like or tuberous appendages. Over time, the tumors undergo sclerosis, meaning they calcify and grow hard.
Symptoms of tuberous sclerosis may be identifiable at birth or may develop over time.
In the United States, as of the early 2000s, there are between 25,000 and 40,000 individuals with tuberous sclerosis. Globally, about 1 to 2 million individuals have the disease. The disease occurs in about one out of every 6,000 newborns. There is no gender, racial, or ethnic predilection.
Causes and symptoms
Tuberous sclerosis occurs when at least one of two genes (either TSC-1 on chromosome 9 or TSC-2 on chromosome 16) is defective. Normally, the two genes produce proteins called hamartin and tuberin, respectively. These proteins seem to serve as inhibitors of tumor growth. When the TS genes are defective or absent, the proteins are either absent or deficient, which allows tumor growth.
Most cases of tuberous sclerosis occur due to spontaneous mutations. This means that the disease does not occur due to the inheritance of an abnormal gene, but rather because the baby's gene is defective for some reason other than inheritance.
The tumors of tuberous sclerosis occur throughout the body, including the brain, heart, lungs, kidneys, eyes, and skin. Other symptoms include seizures, developmental delay , behavior problems, and skin problems.
KIDNEYS Cysts on the kidneys tend to appear during the second or third decade of life. In most cases, they do not interfere with kidney functioning. Rarely, there are so many cysts that the kidneys functioning is impaired, or the cysts bleed, resulting in anemia. Fatty growths within the kidneys (called angiolipomas) may grow so large that they cause pain and/or kidney failure. Rarely, malignant tumors of the kidney (renal cell carcinoma) occur within an existing angiolipoma.
BRAIN Several types of brain tumors can grow, resulting in blockage of the flow of cerebrospinal fluid, fluid backup, headaches, and visual disturbances.
HEART Benign tumors in the heart (rhabdomyomas) may block circulation or may exist uneventfully.
EYES White areas in the retina, called phakomas, are characteristic of the disease (and may aid in diagnosis) but do not result in visual disturbances.
SKIN A variety of skin disorders are noted in tuberous sclerosis, including areas of under-pigmented skin (hypomelanic macules); reddish bumps on the face (facial angiofibromas); raised patches on the forehead (called forehead plaques); areas of rough, thickened skin on the neck or back (shagreen patches); tiny fleshy bumps around or under the toe- or fingernails (ungula or subungual fibromas); skin tags (molluscum fibrosum); flat brown patches.
BEHAVIOR About 33 to 50 percent of all tuberous sclerosis patients have problems such as learning disabilities, severe mental retardation , attention deficit disorder, obsessive-compulsive disorder , autism , aggression, rage, or self-harming behavior.
Tuberous sclerosis is diagnosed when the characteristic tumors are noted in the skin, heart, brain, or kidneys. Many patients come to the healthcare provider's attention after they have begun to have seizures. Further examination with CT and/or MRI scans, ultrasound, and Wood's lamps to view the eyes will reveal the presence of the characteristic tumors of tuberous sclerosis.
As of 2004, no cure was available for tuberous sclerosis. Antiseizure medications may be prescribed, as well as medications to treat attention deficit disorder and obsessive-compulsive disorder. Skin lesions may be removed or reduced via dermabrasive or laser procedures. Surgery may be performed to remove enlarging kidney tumors, to avoid the advent of kidney failure.
Most individuals with tuberous sclerosis have a normal lifespan. The prognosis for their quality of life depends on the severity of their behavioral and cognitive symptoms. Individuals whose symptomatology is confined to kidneys or skin (as opposed to having multiple behavioral symptoms) may do very well.
As of 2004, there was no way to prevent tuberous sclerosis.
Parents of child with tuberous sclerosis should be prepared to answer any questions their child or the child's siblings may have about the disease. Siblings may fear they will catch the disease or perhaps caused it, and may need to reassured that they are not at fault.
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Rosalyn Carson-DeWitt, MD