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Key Points

  • Disease summary:

    • Tuberous sclerosis complex (TSC) is a multiorgan disorder characterized by benign growths called hamartomas that can occur anywhere throughout the body. Hypopigmented macules, facial angiofibromas, shagreen patches, ungual fibromas, and dental pitting are characteristic of the disease. Central nervous system involvement is associated with highest morbidity and clinically manifests as epilepsy, learning disabilities or cognitive impairment, autism and other behavioral disorders, psychiatric disorders, and sleep abnormalities. The hallmarks of cerebral involvement are cortical tubers, subependymal nodules (SENs), and subependymal giant cell astrocytomas (SEGAs). Angiomyolipomas (AMLs) of the kidney, lymphangioleiomyomatosis (LAM) of the lung, and rhabdomyomas of the heart also cause significant morbidity.

  • Hereditary basis:

    • TSC is an autosomal dominant genetic disorder with near 100% penetrance, but clinical severity is highly variable. It is genetically heterogeneous, with mutations in one of two genes (TSC1 or TSC2) causing the disorder. About one-third of cases are familial, the remainder is sporadic. Genetic mosaicism, including germline mosaicism, also exists. Genetic testing is available for affected individuals. Mutation in either gene (TSC1, TSC2) is detected in 85% of cases.

  • Differential diagnosis:

    • The combination of multiple features of TSC is rarely mistaken for other disorders. However, individual features may overlap with those of other syndromes. Hypopigmented macules (ash leaf macules) can occur from many different etiologies; vitiligo, piebaldism, hypomelanosis of Ito, and incontinentia pigmenti are among the differential diagnosis. Renal AMLs and pulmonary LAM can occur sporadically but certainly occur in high association with TSC. Cortical migration defects can occur as an isolated, idiopathic finding unrelated to TSC. Other neurocutaneous disorders, such as neurofibromatosis 1 or 2, have distinct skin manifestations and tumor types which should not be mistaken for TSC.

  • Management:

    • Treatment with the mammalian target of rapamycin (mTOR) inhibitors such as sirolimus and everolimus results in significant shrinking of SEGAs and renal AMLs, and can be an alternative to surgery in some cases. Benefit in lung disease (LAM) has also been demonstrated. Additional studies are ongoing to determine their efficacy for epilepsy and neurocognition in TSC.

Diagnostic Criteria and Clinical Characteristics

Diagnostic Criteria*

  • Clinically definite tuberous sclerosis: two major or one major + two minor features

  • Clinically probable tuberous sclerosis: one major + one minor feature

  • Clinically possible tuberous sclerosis: one major or two minor features

*Genetic confirmation of known disease-causing mutation in either TSC1 or TSC2 gene is also considered sufficient for confirmed diagnosis of TSC. However, failure to identify a disease-causing mutation in TSC1 or TSC2does not exclude the diagnosis if clinical criteria are met.

Clinical Characteristics

Any organ system can be affected in patients with tuberous sclerosis, with central nervous system, skin, kidney, lung, and heart being most common. Many of the features are age dependent.

Central Nervous System

Cortical and subcortical tubers ...

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