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Clinical Features

Tuberous sclerosis follows an autosomal dominant inheritance pattern and results from mutations in the TSC1 or TSC2 genes. The birth incidence is about 1 per 6000. The disease process involves hamartoma formation in multiple organ systems. Neurological, renal and dermatological systems are particularly affected:

  • Dermatological – becomes clinically apparent in the pediatric patient population
    • Hypomelanotic macules (90%)
    • Facial angiofibromas (75%)
    • Shagreen patches
    • Cephalic plaques
    • Ungual fibromas
  • Renal (50-80% collectively)
    • Angiomyolipomas
    • Renal cysts
    • Renal cell carcinoma
    • Oncocytomas
  • Neurological – features
    • Epilepsy
    • Neurocognitive deficits/Intellectual disability
    • Developmental disorders (e.g. autism)

Tumors in the central nervous system (followed by renal disease) are the primary cause of morbidity and mortality in this patient population. A diagnosis of tuberous sclerosis should be considered if one of the following major features is identified: angiofibromas/fibrous cephalic plaque, cardiac rhabdomyoma, cortical dysplasia, hypomelanotic macules, lymphangioleiomyomatosis, multiple renal nodular hamartomas, renal angiomyolipoma, shagreen patch, subependymal giant cell astrocytoma, subependymal nodules or ungual fibromas.

Initial Investigation

Clinical findings lead to a diagnosis of tuberous sclerosis. About 75-90% of patients that meet the diagnostic criteria for tuberous sclerosis have an identifiable pathogenic variant. Among this group of patients, approximately ⅓ have mutations affecting TSC1, and ⅔ affecting TSC2.

Underlying Pathology

Tuberous sclerosis arises from mutations affecting the TSC1 or TSC2 genes which encode proteins that modulate cellular activity via the mTOR signaling pathway. In the CNS, TSC1 and TSC2 regulate neuronal size, axonal growth and sprouting, dendritic arborization, neuronal migration, and cortical lamination.

The CNS manifestations of tuberous sclerosis constitutes the most devastating aspect of the illness. The neurologic features of tuberous sclerosis arise from cortical tubers, subependymal giant cell astrocytomas, subependymal nodules, and other structural abnormalities in the CNS. Cortical tubers are malformations of the cerebral cortex, where the usual hexalaminar structure is disrupted. Cortical tubers are thought to be formed during embryonic brain development.

Common Treatments

There is no cure for tuberous sclerosis. The goal of treatment is to maximize quality of life and minimize complications from the underlying disease process. Everolimus is an FDA approved drug used for the treatment of subependymal giant cell astrocytomas and angiomyolipoma kidney tumors. Anticonvulsants like vigabatrin are used to control seizures. Specialized educational programs may be needed for children with intellectual disability.

Rapamycin is a promising palliative treatment strategy for tuberous sclerosis, though it lacks FDA approval for this purpose. Rapamycin is an immunosuppressant that inhibits the ability of mTOR to phosphorylate downstream targets.

Tuberous sclerosis has historically been undertreated due to the pessimism about outcomes. However, about 10% of patients with tuberous sclerosis possess normal intelligence, and there’s evidence that this number could be increased with early intervention.

References

  1. Orlova KA, Crino PB. The tuberous sclerosis complex. Ann N Y Acad Sci. 2010;1184:87-105.
  2. Schwartz RA, Fernández G, Kotulska K, Jóźwiak S. Tuberous sclerosis complex: advances in diagnosis, genetics, and management. J Am Acad Dermatol. 2007;57(2):189-202.
  3. Ahlsén G, Gillberg IC, Lindblom R, Gillberg C. Tuberous sclerosis in Western Sweden. A population study of cases with early childhood onset. Arch Neurol. 1994;51(1):76-81.