Tuberous Sclerosis Complex (TSC)

Genetics

Tuberous Sclerosis arises from mutation in the TSC1 or TSC2 genes, which code for hamartin and tuberin respectively. These genes form a complex; tuberin acts by activating GTPase which reduces the availability of GTP; GTP is the required by several oncogeneic proteins such as ras and therefore loss of tuberin/hamartin may lead to increased activity of these genes. It also inhibits the activity of mTOR (mammalian target of rapamycin).

TSC1 and TSC2 are both inherited in an autosomal recessive manner. Knudson's two-hit hypothesis applies to malignancies which arise from these germline mutations. About 1/3rd of cases are familial whereas the remainder are sporadic germline mutations.

Phenotype

There is variable phenotypes even between patients in the same pedigree, which is likely due to mosaicism of gene expression in each patient. Major findings include cutaneous and neurological effects but multiple other body systems are involved.

Cutaneous

Characteristic cutaenous lesions include:

  • Hypopigmented macules (ash leaf spots), often on the back
  • Angiofibromas of the face
  • Pigmented plaques of the face and forehead, often present at infancy

Neurological

Multiple anatomical changes can be seen:

  • Subcortical hamartomas, also known as tubers and hence the name.
  • Subependymal nodules and subependymal giant cell tumours/astrocytomas
    • Tumours occur in about 10% of patients and are associated with mass effect and interval change as opposed to nodules
  • White matter heterotopia

Seizures occur in almost all patients, mostly (60%) in the first year of life.
Patients also have neurocognitive impairment and autism is common.

Other Effects

Rhabdomyoma of the heart are often associated with TSC, and about 50% of patents with the disease develop the condition, which usually presents in early childhood with a number diagnosed in utero. They may regress spontaneously and are only symptomatic if their mass impacts on cardiac function.
Angiomyolipomas of the kidney are very common findings, and can cause problems with renal function with enlargement.
Lymphangioleiomyomatosis of the lung causes a pulmoanry-fibrosis like pattern and occurs in adults.
Retinal hamartomas occur in about 50% of patients and are asymptomatic but useful for diagnostic purposes.
Patients are at increased risk of rhabdomyosarcoma, renal cell carcinoma and malignant transformation of subependymal giant cell tumours or cutaneous angiofibromas.

Treatment

Seizures are often the most difficult symptom to control. Brain tumours should be managed by gross total resection where possible. Radiotherapy may induce multiple new malignancies over time and should be avoided when possible. Adjuvant therapy with everolimus may be helpful (mTOR inhibitor), which causes a large reduction in subependymal tumours and nodules in about 1/3rd of patients.

Prognosis

About 1/4 die from tumours or epilepsy and another 1/4 for renal impairment.

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