Tuberous Sclerosis Complex at a Glance
- Autosomal dominant syndrome with variable expressivity.
- Manifested by hamartomatous tumors in multiple organs, including brain (causing seizures), eyes, heart, kidneys, lungs, and skin.
- Skin lesions occur in nearly all individuals and are important for diagnosis.
- Skin lesions include hypomelanotic macules, “confetti” lesions, facial angiofibromas, fibrous facial plaque, shagreen patch, and ungual fibromas.
- Hypomelanotic macules appear at birth or shortly thereafter and are most useful in early diagnosis.
- Although the skin lesions are benign, they may require treatment due to symptoms or disfigurement.
The incidence of tuberous sclerosis complex (TSC) is as high as 1 in 6,000 live births.1,2 It occurs with equal frequency in males and females and in different races and ethnicities. Hereditary transmission is evident in approximately one-third of patients. Sporadic disease occurs in about two-thirds of patients, and this is attributed to de novo mutations.3
TSC is caused by mutations in a tumor suppressor gene, either TSC1 or TSC2.3 Mutations in TSC2 are observed in about three-fourths of patients, and even more commonly in de novo cases.4,5 Patients with mutations in TSC2 tend to exhibit a more severe phenotype.4–7
TSC1 maps to chromosome band 9q34. The 8.6-kb full-length transcript encodes a protein called hamartin or TSC1.8 TSC2 maps to chromosome band 16p13.3. The 5.5-kb transcript encodes a protein called tuberin or TSC2.9 Immediately adjacent to TSC2 on chromosome 16 is PKD1, the gene mutated in polycystic kidney disease. Some patients with TSC have severe, early-onset renal cystic disease, and most of these patients have a contiguous deletion of TSC2 and PKD1.10
Typical of mutations in tumor suppressor genes, the mutations observed in patients with TSC are inactivating mutations located anywhere along the sequence of TSC1 or TSC2. Consistent with Knudson's two-hit hypothesis, most TSC tumors show a second somatic mutation that inactivates the wild-type allele.11,12 TSC1 and TSC2 form a complex that inhibits signaling through the mammalian target of rapamycin (mTOR) pathway (Fig. 140-1). Loss of TSC1/TSC2 function leads to increased mTOR signaling and increased cell growth. Rapamycin is a drug that inhibits mTOR and may be useful for the treatment of internal tumors in TSC.13
Molecular pathogenesis of tuberous sclerosis complex (TSC). A. An example is shown in which a mutation in TSC2 is passed from the father (red square) to the son (red square), whereas the mother (white circle) and another son (white square) are unaffected. B. Skin lesions are observed in the son at the indicated locations. C. A cell from the mother shows two normal alleles for TSC2 on chromosome band 16p13.3. A cell from the son shows the TSC2 mutation inherited from ...