Merck Manual

Please confirm that you are a health care professional

honeypot link

Tuberous Sclerosis Complex (TSC)


M. Cristina Victorio

, MD, Akron Children's Hospital

Last full review/revision Mar 2020| Content last modified Mar 2020
Click here for Patient Education
Topic Resources

Tuberous sclerosis complex is a dominantly inherited genetic disorder in which tumors (usually hamartomas) develop in multiple organs. Diagnosis requires imaging of the affected organ. Treatment is symptomatic or, if central nervous system tumors are growing, sirolimus or everolimus. Patients must be monitored regularly to check for complications.

Tuberous sclerosis complex (TSC) is a neurocutaneous syndrome that occurs in 1 of 6000 children; 85% of cases involve mutations in the TSC1 gene (9q34), which controls the production of hamartin, or the TSC2 gene (16p13.3), which controls the production of tuberin. These proteins act as growth suppressors. If either parent has the disorder, children have a 50% risk of having it. However, new mutations account for two thirds of cases.

Patients with TSC have tumors or abnormalities that manifest at different ages and in multiple organs, including the

  • Brain

  • Heart

  • Eyes

  • Kidneys

  • Lungs

  • Skin

Central nervous system (CNS) tubers interrupt neural circuits, causing developmental delay and cognitive impairment and may cause seizures, including infantile spasms. Sometimes the tubers grow and obstruct flow of cerebrospinal fluid from the lateral ventricles, causing unilateral hydrocephalus. Sometimes tubers undergo malignant degeneration into gliomas, particularly subependymal giant cell astrocytomas (SEGAs).

Cardiac myomas may develop prenatally, sometimes causing heart failure in neonates. These myomas tend to disappear over time and usually do not cause symptoms later in childhood or in adulthood.

Kidney tumors (angiolipomas) may develop in adults, and polycystic kidney disease may develop at any age. Kidney disease may cause hypertension.

Pulmonary lesions, such as lymphangioleiomyomatosis, may develop, particularly in adolescent girls.

Symptoms and Signs

Manifestations vary greatly in severity. Skin lesions are typically present.

Infants with CNS lesions may present with a type of seizure called infantile spasms. Affected children may also have other types of seizures, intellectual disability, autism, learning disorders, or behavioral problems.

Retinal achromic patches are common and may be visible with funduscopy.

Pitting of enamel in permanent teeth is common.

Skin findings include

  • Initially pale, ash leaf–shaped macules, which develop during infancy or early childhood

  • Angiofibromas of the face (adenoma sebaceum), which develop during later childhood

  • Congenital shagreen patches (raised lesions resembling an orange peel), usually on the back

  • Subcutaneous nodules

  • Café-au-lait spots

  • Subungual fibromas, which can develop any time during childhood or early adulthood

Skin Manifestations of Tuberous Sclerosis Complex


  • Clinical criteria

  • Identification of the skin lesions

  • Imaging of affected organs

  • Genetic testing

The International Tuberous Sclerosis Complex Consensus Conference of 2012 defined major and minor criteria for making a definite or possible diagnosis of TSC (1; see table International Tuberous Sclerosis Complex (TSC) Consensus Conference Criteria for the Diagnosis of TSC).

A definite diagnosis of TSC by these criteria requires either of the following:

  • The identification of either a TSC1 or TSC2 pathogenic mutation in DNA from normal tissue

  • Two major features or 1 major feature with ≥ 2 minor features

A possible diagnosis of TSC by these criteria requires the following:

  • Either 1 major feature or ≥ 2 minor features


International Tuberous Sclerosis Complex (TSC) Consensus Conference Criteria for the Diagnosis of TSC



Major features*

Hypomelanotic macules

≥ 3, at least 5 mm in diameter

Angiofibromas (adenoma sebaceum) or fibrous cephalic plaque

≥ 3 angiofibromas

Subungual/ungual fibromas

≥ 2

Shagreen patch

Multiple retinal hamartomas

Cortical dysplasias†

Subependymal nodules

Cardiac rhabdomyoma


Minor features*

“Confetti” skin lesions

Areas of stippled hypopigmentation, typically on the extremities

Pitting of enamel

> 3

Intraoral fibromas

≥ 2

Retinal achromic patch

Multiple renal cysts

Nonrenal hamartomas

* A definite diagnosis of TSC requires either of the following:

  • The identification of either a TSC1 or TSC2 pathogenic mutation in DNA from normal tissue

  • Two major features or 1 major feature with ≥ 2 minor features

A possible diagnosis of TSC requires the following:

  • Either 1 major feature or ≥ 2 minor features

† Includes central nervous system tubers and cerebral white matter radial migration lines.

‡ A combination of the two major clinical features (lymphangioleiomyomatosis and angiomyolipomas) without other features does not meet the criteria for a definite diagnosis.

Adapted from Northrup H, Krueger D, and on behalf of the International Tuberous Sclerosis Complex Consensus Group: Tuberous sclerosis complex diagnostic criteria update: Recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference. Pediatr Neurol 49(4):243–254, 2013. doi: 10.1016/j.pediatrneurol.2013.08.001.

Physical examination is done to check for typical skin lesions. Funduscopy should be done to check for retinal patches.

TSC may be suspected when fetal ultrasonography detects cardiac myomas or when infantile spasms occur.

Cardiac or cranial manifestations may be visible on routine prenatal ultrasonography. MRI or ultrasonography of the affected organs is necessary for confirmation.

Specific genetic testing is available.

Diagnosis reference


Prognosis depends on symptom severity. Infants with mild symptoms generally do well and live long, productive lives; infants with severe symptoms may have serious disabilities.

Regardless of severity, most children show continued developmental progress.


  • Symptomatic treatment

  • Sirolimus or everolimus

Treatment of TSC is both symptomatic and specific:

  • For seizures: Antiseizure drugs (especially vigabatrin for infantile spasms) or sometimes epilepsy surgery

  • For skin lesions: Dermabrasion or laser techniques

  • For neurobehavioral problems: Behavior management techniques or drugs

  • For hypertension caused by renal problems: Antihypertensives or surgery to remove growing tumors

  • For developmental delays: Special schooling or occupational therapy

  • For malignant tumors and some of the benign tumors: Everolimus or sirolimus

Although so far they are approved only for the treatment of subependymal giant cell astrocytomas, growing evidence suggests oral sirolimus and its derivative, everolimus, may be used to prevent and treat most of the complications of TSC. These drugs have been shown in some patients to shrink brain tubers, cardiac rhabdomyomas that are too large to be resected, and facial lesions and to lessen seizures. Topical sirolimus may be helpful for facial angiofibromas (1). Studies using these drugs for these and other complications of TSC are ongoing.

Genetic counseling is indicated for adolescents and adults of childbearing age.

Screening for complications

All patients should be screened regularly to detect complications of TSC early.

Typically, the following is done:

  • MRI of the head to check for intracranial complications at least every 3 years

  • Renal ultrasonography or MRI of the abdomen to check for kidney tumors every 3 years in school-aged children and every 1 to 2 years in adults

  • In girls ≥ 18 years, screening for exertional dyspnea and shortness of breath annually and high-resolution CT every 5 to 10 years

  • Neuropsychologic testing periodically and behavioral screening in children to help plan for support at school and behavioral interventions

Clinical monitoring is also important and sometimes prompts more frequent testing. Development of headaches, loss of skills, or new kinds of seizures may be caused by malignant degeneration or growth of CNS tubers and are indications for neuroimaging.

Treatment reference

  • 1. Darling T: Topical sirolimus to treat tuberous sclerosis complex (TSC). JAMA Dermatol 154(7):761–762, 2018. doi: 10.1001/jamadermatol.2018.0465.

Click here for Patient Education
NOTE: This is the Professional Version. CONSUMERS: Click here for the Consumer Version
Professionals also read

Also of Interest