Tuberous sclerosis affects approximately 1 in 6000 newborns. Males and females are affected equally. Overall, 2 million individuals across all ethnicities are believed to be affected.

Tuberous sclerosis is a genetic condition. Two genes that have been linked to this condition are TSC1 and TSC2. These genes encode two critical proteins called hamartin and tuberin, respectively. Hamartin and tuberin work together to regulate cell growth, differentiation, development, and proliferation. Since TSC1 and TSC2 inhibit abnormal cell growth, they are known as tumor suppressor genes. Defects in either of these genes lead to cell overgrowth or abnormal division. 

Tuberous sclerosis can be inherited in an autosomal dominant manner. Each individual inherits two copies of each gene, one from each parent. An autosomal dominant condition occurs when one defective copy of a gene is enough to cause the condition. Although some affected individuals inherit this disorder from their parents, most cases present in individuals with no family history. These are known as sporadic cases and often occur due to a genetic change in the germ cells (sperm or eggs) of their parents. Individuals with tuberous sclerosis are born with one defective copy of the TSC1 or TSC2 genes. Usually, the healthy gene is enough to produce hamartin and tuberin and keep the cells functioning. However, individuals with one defective copy are more likely to get a mutation in the healthy gene in some cells that will lead to tumour development.

Symptoms of tuberous sclerosis are due to the formation of benign tumours in different organ systems. The particular symptoms experienced by each individual depends on the affected organs. Organs that are most commonly affected are the brain, skin, heart, kidney, eyes, and lungs. 

The brain is among the most commonly affected organs in tuberous sclerosis. Formation of tumours in the brain can cause seizures which are often one of the first symptoms of this condition. In young children, infantile spasms are a common type of seizure observed in this condition. Infantile spasms are seizures characterized by a sudden, brief stiffening of the body that causes a movement of the arms, head, and legs. Growth in the brain may block the flow of the fluid inside the brain and lead to a condition called hydrocephalus or the excessive accumulation of fluid in the brain. If this occurs, individuals may experience headaches, nausea, and blurred vision. Additionally, some individuals may experience varying levels of developmental and intellectual disability. Aggression, attention deficit hyperactivity disorder, autism spectrum disorder, obsessive-compulsive disorder, and other behavioral problems are also possible. 

Skin lesions are also common in tuberous sclerosis. Many affected individuals have areas of pale skin that is lighter than the surrounding skin. These are called hypomelanic macules and are due to an absence of pigment-producing cells in that region and may appear anywhere on the body. Furthermore, small red spots may appear on the face called facial angiofibromas. These spots may be flat or raised and may resemble acne in a butterfly pattern. In some individuals, thick, leathery skin patches form that feel like an orange peel. These patches commonly form on the lower back and the back of the neck. Additionally, fleshy tumours may form under and around the nails that might be harmless or cause bleeding.

In most individuals, the kidney may also be involved. Depending on the extent of kidney involvement, individuals may experience high blood pressure, bleeding, or more serious complications such as kidney failure. In the majority of affected individuals, benign tumours called angiolipomas form on the kidney, usually between the ages of 15 to 30 years old. These tumours may be small and harmless but in some individuals, they may grow in size or number and interfere with kidney function and even lead to kidney failure. Rarely, these nodules may rupture and bleed and cause pain and anemia.

If the lungs are involved, individuals may experience coughing or shortness of breath. Tumors affecting the lungs are more common in women than men. Less commonly, lung involvement may lead to lung failure which occurs when not enough oxygen is passed from the lungs to the blood. This may be due to the collapse of the lungs or the accumulation of fluid in them.

Some infants present with growths in the heart that develop before birth and often shrink as the child grows. Sometimes, growths in the heart can impair the proper function of the heart and cause heartbeat irregularities (arrhythmia) or obstruct blood flow in the heart. 

White patches may appear in the retina or the light-sensitive layer that covers that back of the eyes. These growths usually do not interfere with vision. Rarely, they may grow in size and cover essential areas of the retina in which case, vision may be affected. 

In rare cases, affected individuals may have a higher risk of developing cancer in the brain and the kidneys.

The diagnosis of tuberous sclerosis is based on clinical examination, computed tomography (CT) scan, and magnetic resonance imaging (MRI). The presence of seizures, developmental delay, or skin patches may indicate the diagnosis of tuberous sclerosis. The presence of nodules in the brain or the kidney or the presence of a heart tumor at birth may also suggest tuberous sclerosis. This condition may be diagnosed in infants, especially if a heart tumor is present at birth. However, many individuals are not diagnosed until later in life when symptoms develop.

The skin of individuals with a suspected diagnosis may be examined under ultraviolet lamps to detect white patches that glow under UV light and may not be visible in infants or pale-skinned individuals. A CT scan or MRI of the head, as well as a CT of the chest, an echocardiogram of the heart, and an ultrasound of the kidneys may also be performed to look for nodules and growths in these organs. These are all imaging techniques that visualize the inner parts of the body. A CT scan uses x-rays, MRI uses magnetic fields, echocardiogram, and ultrasound both use ultrasound waves for visualization. 

Molecular genetic testing can confirm the diagnosis of tuberous sclerosis if a mutation is identified in TSC1 or TSC2.

Treatment of tuberous sclerosis is symptomatic. Seizures can be controlled by anti-seizure medications. The specific type of medication depends on the type and severity of the seizures and the age of the affected individual. If the seizure does not respond or stop responding to medications, surgery may be required. In some cases, a vagal nerve stimulator may be helpful in controlling seizures. A vagal nerve stimulator is a device that sends electrical impulses to the vagus nerve, one of the many nerves that exit the spinal cord. This device helps regulate electrical connections of the brain.

If respiration is affected, oxygen therapy may benefit the affected individual. This is a treatment where oxygen is administered through a mask and is helpful for individuals who cannot obtain enough oxygen independently. 

 Surgery may be required in some cases, particularly in certain types of brain involvement and as well as when kidney nodules may rupture and lead to bleeding. If kidney nodules develop into cancer, surgery may be required. Sometimes, cutting off the blood supply to the kidney tumor may cause a reduction in its size.

Individuals with intellectual and developmental disabilities may benefit from educational support, occupational therapy, and other forms of appropriate programs. 

The prognosis for tuberous sclerosis differs among individuals. Some may only experience mild symptoms with a normal life expectancy and without a significant impact on the quality of life, others may be severely affected and may experience life-threatening complications. Usually individuals with a mutation in TSC2 experience more severe symptoms than those with a TSC1 mutation.

National Institute of Neurological Disorders and Stroke. Tuberous Sclerosis Fact Sheet. 2020. Available from https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Tuberous-Sclerosis-Fact-Sheet

Genetics Home Reference. Tuberous sclerosis complex. 2017. Available from https://ghr.nlm.nih.gov/condition/tuberous-sclerosis-complex#synonyms

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