Disorder Definitions

Tuberous sclerosis complex (TSC) is a multisystem autosomal dominant genetic disorder caused by mutations in the TSC1 or TSC2 genes. It is characterized by benign, highly vascular, hamartoma growths. Lesions occur in the eyes, brain, kidneys, heart, liver, lungs and skin, leading to seizures, epilepsy, intellectual disability, autism, renal and pulmonary complications (Gomez et al, 1999; Astrinidis and Henske, 2005; Inoki et al, 2005; Kwiatkowski and Manning, 2005). The brain is almost invariably affected and brain lesions are the primary cause of morbidity in this disease in childhood.

Symptoms

The most common symptoms of TSC are seizures and developmental delay as well as benign tumors and lesions, which can affect virtually every organ system of the body including the brain, kidneys, heart, lungs, eyes, skin, and other organs. In many instances, symptoms of TSC will be apparent in the first six months of life.

Brain and Neurological Function:

In 95% of individuals with TSC, the brain is somehow affected. This usually takes the form of cortical tubers, subependymal nodules (SEN) and subependymal giant cell astrocytomas (SEGA), which can be detected by brain imaging.

Epilepsy is by far the most common medical condition in TSC, occurring in 80-90% of individuals. In about one-third of individuals with TSC, epilepsy starts out as infantile spasms. Peak onset occurs at about 4-6 months of age.

Individuals with TSC have an increased risk of having neurodevelopmental and behavioral impairment. Although approximately 50% of individuals with TSC have normal intelligence, developmental delay and learning disabilities are commonly found in children with TSC. Additionally, up to 60% of individuals with TSC can develop autism.

Skin:

Skin lesions, including those found on the face, body and nails, are found in almost all individuals with TSC. The earliest sign may be white skin patches (hypomelanotic macules), which are best seen under ultraviolet light. As a child grows older, a characteristic facial rash across the nose and cheeks may appear.

Heart:

Cardiac (heart) involvement is common in TSC and is found in up to 66% of the individuals. Benign heart tumors (cardiac rhabdomyomas) are often an early sign of TSC. Fortunately, these tumors often regress spontaneously, shrinking or completely disappearing with time.

Kidney:

Kidney lesions occur in over half of all children at the time of initial evaluation. Benign renal lesions, called angiomyolipomas, account for 75% of abnormalities, are made up of vascular tissue, smooth muscle, and fat. They usually grow very slowly and may not be problematic until young adulthood. Renal cysts are also common in TSC. Larger or numerous angiomyolipoma or cysts can reduce renal function or increase the risk for hypertension. Larger angiomyolipoma increases the likelihood of renal aneurysms that may cause bleeding or pain that if undiagnosed or untreated can be life-threatening.

Diagnosis

Clinical diagnosis of TSC is based on a careful physical exam in combination with imaging of the brain, heart and kidneys. The physician will carefully examine the skin for the wide variety of skin lesions, often using an ultraviolet light called a Wood’s lamp which may be useful for finding skin features that can be hard to see on infants or individuals with pale skin.

There is no single clinical feature specific to the condition. In addition, many features of TSC, such as seizures and developmental delay, are seen in individuals without TSC. Therefore, a constellation of features is necessary for the diagnosis, and an increasing number of features make the clinical suspicious of TSC more likely. Please refer to for a summary of the clinical and genetic diagnostic criteria.

Recently, genetic testing for TSC has become more readily available, and a positive genetic test can be considered diagnostic.

Treatment and Prognosis

There is no cure for TSC, though symptoms can be managed through a number of treatments. Anti-epileptic medications are available to control seizures. Pharmacologic inhibitors of mTOR, such as everolimus and sirolimus, can be used to treat SEGAs, refractory epilepsy, kidney angiomyolipoma, and LAM disease of the lungs. Other treatments include medications for skin findings and medications or interventional treatments for behavioral problems associated with TSC. Surgery may be required for complications related to brain lesions such as cortical tubers, SENs, or SEGAs.