Tuberous Sclerosis Complex
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- Tuberous sclerosis complex (TSC) is a genetic neurocutaneous syndrome (phakomatosis).
- Classic triad: intellectual disability, facial angiofibromas, and seizures; multiple hamartomas
- System(s) affected: nervous, skin, renal/urologic, pulmonary, cardiovascular, musculoskeletal, ophthalmologic, exocrine
- Synonym(s): Bourneville disease
Prenatal diagnosis by mutational analysis is possible when a familial mutation has been identified.
Etiology and Pathophysiology
- Mutations in either of two genes—TSC1 and TSC2—that code for hamartin and tuberin, respectively. These form a heterodimer that acts as a tumor suppressor.
- Decreased production of TSC proteins and excessive cell proliferation results in tuber formation.
- Loss of gene function is associated with hyperactivity of the mechanistic target of rapamycin complex 1 (mTORC1) signaling.
- In TSC, some hamartomas show loss of heterozygosity on chromosome 9q34.13 or 16p13.3.
- The patient has inherited a mutation or a deletion in one copy of the gene but develops a lesion only when there is a somatic mutation in the other.
- This two-hit mechanism explains the variable expressivity and seems to apply to cardiac rhabdomyomas, renal angiomyolipomas, and subependymal giant cell tumors (SGCTs) but not to cerebral tubers.
- Autosomal dominant with complete penetrance and variable expressivity (OMIM 191100 and 191092)
- 2/3 of cases result from new mutations. Somatic mosaicism occurs in 2–10% of de novo TSC.
- Two chromosomal loci: TSC1 (9q34.13); TSC2 (16p13.3) (TSC2 3 times as common as TSC1)
- Genetic testing is recommended when TSC is suspected but not clinically confirmed (2)[A] and for all new patients with TSC (1)[C].
- Clinical phenotype of TSC1 mutations generally is milder than that of TSC2 mutations (3).
- There is a contiguous gene deletion involving large deletions and rearrangements of TSC2 and PKD1 (causing polycystic kidney disease).
- Family history. Expressivity is variable, even within a family.
- If neither parent meets criteria for TSC, the recurrence risk is 1–2% per child.
Commonly Associated Conditions
- Intellectual disability (55–70%): usually associated with history of seizures, autism (40–50%)
- Cortical tubers 82%, subependymal nodules (78%), subependymal giant cell astrocytomas (SEGAs) (24%) (4)
- Seizures (83%), 78% of whom diagnosed ≤2 years old
- 25% of patients with infantile spasms have TSC.
- TAND: interrelated functional and clinical manifestations of brain dysfunction common in TSC: aggressive behaviors, autism spectrum disorders, intellectual disabilities, psychiatric disorders, neuropsychological deficits, and school and occupational difficulties (1,2)
- Cardiac rhabdomyomas (34–67%)
- Lymphangioleiomyomatosis (LAM) of the lung, especially in women (up to 80%) (4)
- Cardiac arrhythmias
- Renal insufficiency, renal angiomyolipomas
- Retinal lesions: hamartomas (up to 75%), achromic patches (39%)