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Tuberous sclerosis

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Other Names: Tuberous sclerosis; Bourneville syndrome

Tuberous sclerosis complex (TSC) is a rare multisystem autosomal dominant genetic disease that causes non-cancerous tumours to grow in the brain and on other vital organs such as the kidneys, heart, eyes, lungs, and skin.

A woman with tuberous sclerosis
A woman with tuberous sclerosis

Clinical features

It usually affects the central nervous system. In addition to the benign tumors that frequently occur in TSC, other common symptoms include seizures,impaired intellectual development, behavior problems, and skin abnormalities.

Presentation

TSC-Frequency-Signs-Childhood
TSC-Frequency-Signs-Childhood

TSC may be present at birth, but signs of the disorder can be subtle and full symptoms may take some time to develop.

Types

Three types of brain tumors are associated with TSC: cortical tubers, which generally form on the surface 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 block the flow of fluids within the brain. Cause Tuberous sclerosis complex (TSC) is caused by the TSC1 or TSC2 gene not working correctly. DNA changes known as pathogenic variants are responsible for making genes work incorrectly or not at all.

Inheritance

Autosomal dominant pattern, a 50/50 chance.

Tuberous sclerosis complex (TSC) is inherited in an autosomal dominant pattern. All individuals inherit two copies of each gene.[5] Autosomal means the gene is found on one of the numbered chromosomes found in both sexes. Dominant means that only one altered copy of a gene is necessary to have the condition. The alteration can be inherited from either parent. Sometimes an autosomal dominant condition occurs because of a new genetic alteration (de novo) and there is no history of this condition in the family.

Each child of an individual with an autosomal dominant condition has a 50% or 1 in 2 chance of inheriting the alteration and the condition. Typically, children who inherit a dominant alteration will have the condition, but they may be more or less severely affected than their parent. Sometimes a person may have a gene alteration for an autosomal dominant condition and show no signs or symptoms of the condition.

Symptoms

The following list includes the most common signs and symptoms in people with tuberous sclerosis complex (TSC). These features may be different from person to person. Some people may have more symptoms than others and symptoms can range from mild to severe. This list does not include every symptom or feature that has been described in this condition. Signs and symptoms include: Skin findings:

  • Small bumps made up of blood vessels (angiofibromas)
  • Patches of thickened, rough skin (shagreen patches)
  • Growths under the fingernails and toenails (ungual fibromas)
  • Light colored skin patches (hypomelanonic macules)
  • Brain findings:
  • Benign brain tumor (astrocytoma)
  • Abnormal organization of the brain (cortical dysplasia)
  • Nodules in the brain (subependymal nodules)
  • Seizures

Other systems:

  • Benign growth in the retina (retinal hamartoma)
  • Heart muscle tumor (cardiac rhabdomyoma)
  • Formation of unusual clumps of cells in the lungs (pulmonary lymphangiomyomatosis)
  • Kidney growths (renal angiomyolipoma)
  • Developmental delay
  • Intellectual disability
  • Behavioral issues

Symptoms of tuberous sclerosis complex begin before birth and might be noted on ultrasound, such as tumors in the brain and heart (subependymal nodules and cardiac rhabdomyomas). Seizures, intellectual disability, and developmental delay usually appear in childhood. Other symptoms that might develop in childhood include skin changes and kidney symptoms caused by tumors. Brain tumors usually grow during childhood and in teen years, which may lead to other concerns, such as hydrocephalus. In adulthood, kidney and pulmonary symptoms become more common.

Diagnosis

Diagnosing TSC is based upon clinical criteria. The first clue may be the presence of seizures or delayed development. In other cases, the first sign may be white patches on the skin (hypomelanotic macules) or the identification of cardiac tumor rhabdomyoma.

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 retinal lesions. A small hand-help lamp that uses black light, otherwise known as ultraviolet light, may show hypomelanotic macules which are sometimes hard to see on infants and individuals with pale or fair skin. A doctor experienced in the diagnosis of TSC should evaluate a potential patient.

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

Treatment

There is no cure for TSC, although treatment is available for a number of the symptoms. Antiepileptic drugs may be used to control seizures. Vigabatrin is a particularly useful medication in TSC and has been approved by the U.S. Food and Drug Administration (FDA) for treatment of infantile spasms in TSC, although it has significant side effects. The FDA has approved the drug everolimus (Afinitor®) to treat subependymal giant cell astrocytomas (SEGA brain tumors) and angiomyolipoma kidney tumors, in addition to intractable seizures (seizures not controlled well by medicine). Specific medications may be prescribed for behavior problems. Intervention programs including special school programs and various therapies (such as physical, occupational, and speech therapies) may benefit individuals with special needs and developmental issues. Surgery may be needed in case of complications connected to tubers, subependymal nodules, or SEGA, as well as in risk of hemorrhage from kidney tumors. Respiratory insufficiency due to LAM can be treated with supplemental oxygen therapy or lung transplantation, if severe.

Because TSC is a lifelong condition, individuals need to be regularly monitored by a doctor to make sure they are receiving the best possible treatments. Due to the many varied symptoms of TSC, care by a clinician experienced with the disorder is recommended.

Basic laboratory studies have revealed insight into the function of the TSC genes and have led to use of rapamycin (mTOR) inhibitors and related drugs for treating some of the manifestations of TSC.

The medication(s) listed below have been approved by the Food and Drug Administration (FDA) as orphan products for treatment of this condition.

  • Everolimus (Brand name: Afinitor) approved for the adjunctive treatment of adult and pediatric patients age 2 years and older with tuberous sclerosis complex (TSC)-associated partial-onset seizures. April 2012 approved for the treatment of adults with renal angiomyolipoma and tuberous sclerosis complex (TSC) not requiring immediate surgery. October 2010 approved for the treatment of patients with subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis who require therapeutic intervention but are not candidates for curative surgical resection.
  • Vigabatrin (Brand name: Sabril)For infantile spasms (IS) 1 month to 2 years of age

Prognosis

The prognosis for individuals with TSC depends on the severity of symptoms. Individuals with mild symptoms generally do well and live long productive lives, while individuals with the more severe form may have serious disabilities.

Complications

In rare cases, seizures, infections, or tumors in vital organs such as the kidneys and brain can lead to severe complications and even death. However, with appropriate medical care, most individuals with the disorder can look forward to normal life expectancy.

NIH genetic and rare disease info

Tuberous sclerosis is a rare disease.

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