What are the characteristics of Tuberous Sclerosis Complex (TSC)?

Characteristics of Tuberous Sclerosis Complex (TSC)

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by the presence of proliferative lesions throughout multiple organ systems, with major neurological and developmental effects in most patients and tumor development in various organs including the brain, kidneys, heart, skin, and lungs. 1

Genetic Basis and Prevalence

• TSC is caused by mutations in the TSC1 and TSC2 genes that inactivate the genes' tumor-suppressive function and drive hamartomatous cell growth 1, 2
• The incidence of TSC at birth is approximately 1 in 5,800, resulting in over one million affected patients worldwide 1
• Two-thirds to three-fourths of individuals with TSC have de novo mutations 1

Major Organ System Involvement

Neurological Manifestations

• Brain lesions in TSC are complex and include subependymal nodules, cortical hamartomas, areas of focal cortical hypoplasia, and heterotopic gray matter 1
• Epilepsy is a leading cause of mortality in TSC patients 3
• Less than 40% of patients have the classic triad of facial angiofibromata, developmental delay, and intractable epilepsy 1

Kidney Manifestations

• Kidney disease is the most common cause of death in adults with TSC 1, 3
• Three major kidney phenotypes occur in TSC patients:
  • Angiomyolipomata (70-80% of patients) 1, 4
  • Cystic kidney disease (approximately 50% of patients) 1
  • Renal cell carcinoma (3-5% of patients) 1
• Approximately 40% of adult patients with TSC have a low glomerular filtration rate (GFR) 1
• The median ages for detection of cysts and angiomyolipomata are 3 years and 8-13 years respectively, but both can develop in the first months of life 1

Cardiac Manifestations

• About two-thirds of newborns with TSC have one or more cardiac rhabdomyomas 1
• Cardiac rhabdomyomas are largest during the neonatal period and typically regress with time 1, 5

Skin Manifestations

• Skin lesions occur in nearly 100% of individuals with TSC, although none are pathognomonic 1
• Facial angiofibromata are a common skin manifestation 3, 6

Ocular Manifestations

• Retinal lesions are present in 87% of individuals with TSC 1
• These may be difficult to detect without dilating the pupils and using indirect ophthalmoscopy 1

Diagnostic Approach

• Clinical diagnostic criteria involve combinations of major and minor criteria 1
• Referral for genetic evaluation should be considered for any individual with a personal history of or first-degree relative with any two criteria from the major or minor diagnostic criteria lists 1
• Genetic testing is valuable for confirming diagnosis and for family planning 3

Treatment Considerations

• mTOR inhibitors (sirolimus and everolimus) are effective treatments for various TSC manifestations 2
• Everolimus is approved for subependymal giant cell astrocytomas and renal angiomyolipomas in patients with TSC 2
• Early mTOR inhibition may prevent the development of TSC lesions and alter the natural history of the disease 6
• A coordinated multidisciplinary approach involving specialists from neurology, nephrology, pulmonology, dermatology, and other disciplines is essential for management 3

Monitoring Recommendations

• Regular kidney monitoring from the point of diagnosis, even in young children 1
• Annual standardized office blood pressure measurements for all patients 3
• Annual assessment of kidney function and proteinuria in adults and children with kidney involvement 3
• Regular neurological monitoring for seizures and developmental issues 3

Common Pitfalls and Caveats

• TSC is often not recognized by clinicians without specialist knowledge 1
• Normal kidney imaging and GFR in young children do not preclude future development of kidney lesions 3
• In patients with low muscle mass due to severe neurological complications, standard creatinine-based equations can overestimate eGFR 3
• Avoid nephron loss during interventional procedures 3