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Tuberous Sclerosis Complex (TSC)

By

M. Cristina Victorio

, MD, Akron Children's Hospital

Last full review/revision Aug 2021| Content last modified Aug 2021
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Tuberous sclerosis complex is a dominantly inherited genetic disorder in which tumors (usually hamartomas) develop in multiple organs. Diagnosis requires specific clinical criteria and imaging of the affected organ. Treatment is symptomatic or, if central nervous system tumors are growing, drug therapy with 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

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

Symptoms and Signs of TSC

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

Retinal achromic patches as well as retinal hamartomas 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

Diagnosis of TSC

  • Clinical criteria

  • Identification of the skin lesions

  • Imaging of affected organs

  • Molecular genetic testing

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

  • The identification of either a TSC1 or TSC2 pathogenic mutation by molecular genetic testing

  • 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

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

TSC may be suspected when fetal ultrasonography detects cardiac rhabdomyomas 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 for TSC

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.

Treatment of TSC

  • Symptomatic treatment

  • Sirolimus or everolimus

Treatment of TSC is both symptomatic and specific:

Although so far they are approved only for the treatment of subependymal giant cell astrocytomas Astrocytomas Astrocytomas are childhood central nervous system tumors that develop from astrocytes. Diagnosis is based on MRI. Treatment is a combination of surgical resection, radiation therapy, and chemotherapy... read more (SEGAs), 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 Treatment reference Tuberous sclerosis complex is a dominantly inherited genetic disorder in which tumors (usually hamartomas) develop in multiple organs. Diagnosis requires specific clinical criteria and imaging... read more Treatment reference ). 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 (eg, SEGAs) 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 for life in affected adults

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

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

  • Echocardiography at least every 3 years for asymptomatic children and adolescents with cardiac rhabdomyomas

Regular monitoring must be continued until cardiac rhabdomyomas have regressed.

Clinical monitoring is also important and sometimes prompts more frequent testing. Development of headaches, loss of skills, or new types 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

Drugs Mentioned In This Article

Drug Name Select Trade
AFINITOR
SABRIL
RAPAMUNE
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