Description

• 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

Pregnancy Considerations
Prenatal diagnosis by mutational analysis is possible when a familial mutation has been identified.

Epidemiology

Incidence

• 6.8 to 12.4/10,000 live births (1)
• Predominant age: Clinical expression is variable; usually is diagnosed during the 1st decade of life
• No gender predominance

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.

Genetics

• 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)[C] 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).

Risk Factors

• Family history. Expressivity is variable, even within a family.
• If neither parent of an affected child meets criteria for TSC, the recurrence risk is 1–2% per child.

General Prevention

Genetic counseling

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%)
• 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%)