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Tuberous Sclerosis

by Margaret C. McBride, MD

Tuberous sclerosis (TS) is a dominantly inherited genetic disorder in which tumors (usually hamartomas) develop in multiple organs.

TS occurs in 1 of 6000 children; 85% of cases involve mutations in the TSC1 gene (9q34) or the TSC2 gene (16p13.3). If either parent has the disorder, children have a 50% risk of having it. However, new mutations account for two thirds of new cases.

Patients with TS (sometimes called TS complex) have tumors or abnormalities that manifest at different ages and in multiple organs, including the brain, heart, eyes, kidneys, lungs, and skin.

CNS tubers interrupt neural circuits, causing developmental delay and cognitive impairment and may cause seizures, including infantile spasms. Sometimes the tubers grow and obstruct CSF flow from the lateral ventricles, causing unilateral hydrocephalus.. Sometimes tubers undergo malignant degeneration into gliomas, particularly subependymal giant cell astrocytomas.

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. Fetal ultrasonography may detect cardiac myomas, or infants may present with a type of seizure called infantile spasms (see Infantile Spasms). Affected children may also have other types of seizures, intellectual disability, autism, learning disorders, or behavioral problems. Retinal 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

Diagnosis

  • Identification of the skin lesions

  • Imaging of affected organs

  • Genetic testing

TS may be suspected when fetal ultrasonography detects cardiac myomas or when infantile spasms occur. Physical examination is done to check for typical skin lesions. 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.

Prognosis

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

  • Symptomatic treatment

  • Everolimus

Treatment is both symptomatic and specific:

  • For seizures: Anticonvulsants (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

All patients should be screened regularly to detect complications early. Typically, the following is done:

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

  • Renal ultrasonography to check for kidney tumors every 3 yr in school-aged children and every 1 to 2 yr in adults

  • Chest x-ray in girls in their late teens

  • Neuropsychologic testing periodically in children to help plan for support at school

Use of everolimus to prevent some complications of TS is under study.

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.

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

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