What is Tuberous Sclerosis Complex?

Tuberous Sclerosis Complex (TSC) is a genetic disorder that occurs in 1 out of 6,000 people and can involve multiple organs in the body, including the brain, heart, kidneys, lungs, eyes, and skin. The disorder may present at any age and is often diagnosed based on specific clinical criteria and/or genetic testing.

Common Features (Major [M] and Minor [m]):

Brain

  • Cortical tubers (M): abnormally developed regions of brain tissue
  • Subependymal nodules (M): small regions of abnormal brain tissue in the ventricles of the brain
  • Giant cell astrocytoma (M): lesions that can grow and block flow of spinal fluid in the brain (found in up to 20% of patients with TSC)
  • Autism: 25 to 50% of patients with TSC may develop autism, along with other delays in development
  • Seizures: most common presenting sign of TSC occurring in 90% of patients

Heart

Rhabdomyomas (M): growths in the heart that are a common feature in newborns diagnosed with TSC. Typically these get smaller with age, but can present with irregular heart rates or alteration of blood flow from the heart.

Lungs

Lymphangiomyomatosis (M): occurs in late adolescence/adulthood and affects females with TSC. May present with chest pain, shortness of breath, or spontaneous pneumothorax.

Kidneys

  • Renal cysts (m) and renal angiomyolipomas (M): present in 70 to 90% of patients with TSC at some point in their lifetime
  • Renal cell carcinoma: present in only 2 to 3% of patients with TSC

Skin

  • Hypomelanotic macules/”ash-leaf spots” (M): small oval or leaf shaped patches of pale/white skin. Most common skin finding in TSC present in up to 98% of patients.
  • Shagreen patch (M): irregular, rough patch of skin most often located over the lower back or thigh. Occurs in approximately 50% of patients with TSC greater than 5 years old and is usually evident by age 10 years.
  • Facial angiofibromas (M): small pink/red bumps found symmetrically across the nose/cheeks. Can be confused with acne.
  • Fibrous plaques (M): yellow-brown patches seen on the scalp/forehead
  • Ungual/periungual fibromas: flesh-colored/pink bumps seen in the nail plate or on the side of the nail. Typically appear around adolescence.
  • Dental lesions: dental pits (m) occur in 90% of patients. Gingival fibromas (m) are small fibrous nodules that appear on the gums.

Eyes

Retinal hamartomas (m): present in up to 50% of patients, rarely change, and rarely cause vision loss

What do seizures in TSC look like?

Patients with TSC may present with a variety of seizure types. One of the most important and common types is infantile spasms that typically present in the first year of life (peak 4 to 8 months). Infantile spasms are characterized by sudden and brief extension or flexion of the extremities lasting just seconds at a time. The seizures often occur in clusters over several minutes and occur more upon awakening or as the infant is going to sleep.

Focal (or partial) seizures are also very common in TSC and can present with a variety of appearances. Focal seizures can present with forced eye or head deviation, rhythmic jerking of an extremity, change in response, or evolve to a generalized convulsive (tonic-clonic) seizure.

Patients with TSC may also present with tonic seizures (brief tonic extension of the extremities, sometimes resulting in a fall), atonic seizures (sudden loss of muscle tone resulting in fall), myoclonic seizures (brief jerks of the extremities that may result in fall, stumble, or dropping objects), and absence seizures (brief periods of decreased response).

The epilepsy of TSC often progresses to become intractable – meaning failure to be controlled with antiepileptic drugs. Other methods of treatment, including dietary therapy, neuromodulation, and epilepsy surgery, can be used to treat some patients.

Is TSC inherited?

TSC is caused by mutations in one of two genes, TSC1 and TSC 2, in 70% of cases. TSC is an autosomal dominant disorder, meaning you only need one mutated gene to have disease. Patients with TSC have a 50% chance of passing on the disease to their children. Approximately 1/3 of cases are inherited from parents, while the other 2/3 occur spontaneously. 

How is TSC diagnosed?

TSC is diagnosed based on physical findings found during an exam and results of imaging studies. The clinical criteria are divided into major (M) and minor feature (m):

  • Definite TSC: 2 major features OR 1 major and 2 or more minor
  • Possible: Either 1 major or 2 or more minor features

The presence of a mutation in the TSC1 or TSC2 gene known to cause disease is also sufficient to make a diagnosis of definite TSC. Note that over 1,200 variants of TSC1 and TSC2 are reported and not all are known to cause disease.

How is TSC treated?

Routine Monitoring

The primary goal of TSC treatment is routine monitoring of disease manifestations. As a result, patients should get scheduled testing, as new symptoms can arise over time. Typical recommended testing includes:

  • MRI brain with and without contrast every 1 to 3 years
  • Electroencephalogram (EEG) at initial diagnosis and when seizures initially present
  • Renal MRI at the time of initial diagnosis and every 1 to 3 years
  • Electrocardiogram (EKG) at diagnosis and then every 3 to 5 years
  • Echocardiogram
  • Pulmonary Function testing – recommended for females greater than 18 years of age and symptomatic adult males
  • High resolution chest CT – recommended for females greater than 18 years of age and symptomatic adult males
  • Routine skin, eye, and dental exams
  • Routine neurodevelopmental and behavioral screening

Epilepsy Treatment

Epilepsy can be treated with a variety of antiepileptic drugs. For infantile spasms and intractable focal seizures, vigabatrin can be especially useful. Most other antiepileptic drugs will have some efficacy against seizures in TSC, though many patients become intractable to medicines.

As a result, other therapies that can be used include the ketogenic diet, neuromodulation (i.e., vagal nerve stimulator), and epilepsy surgery.

Immunosuppresant Therapy

Several immunosuppressant drugs that work on the mTOR pathway (the pathway disrupted in TSC) can be useful for TSC therapy. Sirolimus and everolimus have been used to treat subependymal giant cell astrocytomas, facial angiofibromas, and more recently have shown some efficacy for the treatment of epilepsy.

What is the outlook for persons with TSC?

The prognosis of TSC is highly variable and depends on the organs involved and severity of symptoms. With early recognition of TSC and appropriate monitoring of symptoms, most patients can have a normal life expectancy.

Neurologic symptoms carry the most significant impact to prognosis. At least 50% of patients will have learning disabilities with 30% having severely impaired IQ. Refractory epilepsy increases the risk of impaired neurodevelopment and early death.

The presence of mutations in TSC2 has also been associated with more severe symptoms. Routine monitoring can help avoid complications secondary to involvement of other organ systems.

Authored By: 
M. Scott Perry MD and Angel W. Hernandez MD