Tuberous sclerosis complex
Autosomal dominant multisystem disorder from TSC1 (hamartin) or TSC2 (tuberin) mutations that unchecks mTOR signaling and drives hamartomas in the brain, skin, heart, kidney, and lungs. Diagnosis is clinical, using major and minor criteria; seizures dominate the neurologic picture and mTOR inhibitors treat both refractory epilepsy and growing tumors.
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What this article covers
- Overview
Multisystem hamartoma disorder: tuberous sclerosis complex (TSC) is an autosomal dominant disease from a loss-of-function mutation in TSC1 (hamartin) or TSC2 (tuberin), tumor suppressor genes whose…
- Epidemiology
Birth incidence: roughly 1 in 6,000 to 1 in 10,000 live births, with no sex or ethnic predilection.
- Risk factors
Family history: a first-degree relative with TSC confers the highest risk given autosomal dominant transmission; genetic counseling and TSC1/TSC2 testing are indicated for at-risk relatives.
- Pathophysiology
Loss of the hamartin-tuberin brake on mTOR: hamartin and tuberin form a complex that inactivates Rheb, an upstream activator of mTOR complex 1 (mTORC1); when either gene is mutated, Rheb stays active…
- Clinical features
Diagnosis rests on a set of clinical criteria, not one test: major and minor features across skin, brain, cardiac, renal, pulmonary, and ocular findings define the syndrome.
- Differential diagnosis
Neurofibromatosis type 1 (NF1): shares café-au-lait macules and a predisposition to CNS tumors, but features Lisch nodules, cutaneous neurofibromas, and optic gliomas rather than angiofibromas…
- Diagnosis
Clinical diagnostic criteria establish the diagnosis: definite TSC is diagnosed with two major features, or one major feature plus two or more minor features, from the consensus criteria; a…
- Management
First step at diagnosis: establish multidisciplinary surveillance, coordinating neurology, nephrology, cardiology, pulmonology, dermatology, and ophthalmology around the baseline survey obtained during workup.
- Complications
Status epilepticus and drug-resistant epilepsy: poorly controlled seizures are the leading driver of long-term morbidity and are associated with intellectual disability when onset is in infancy.
- Prognosis
Highly variable, driven mainly by seizure burden: patients with well-controlled epilepsy and no SEGA or major organ complications can have normal life expectancy and preserved cognition; early-onset…
- Prevention
No primary prevention exists since TSC is a germline genetic disorder; management is entirely secondary prevention through surveillance and early treatment.
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Related articles
- Neurofibromatosis type 1
Autosomal dominant neurocutaneous disorder from NF1 tumor suppressor mutations causing cafe-au-lait macules, neurofibromas, Lisch nodules, and optic glioma; diagnosed clinically by consensus criteria and managed with surveillance, surgery for symptomatic tumors, and selumetinib for inoperable plexiform neurofibromas.
- Epilepsy
Epilepsy is a disease of recurrent unprovoked seizures, defined as two unprovoked seizures more than 24 hours apart or one unprovoked seizure with at least a 60% recurrence risk; treatment is guided by seizure type, with levetiracetam or lamotrigine preferred first-line for most adults.