Tuberous Sclerosis Complex (TSC): Definition and Clinical Implications
Tuberous Sclerosis Complex (TSC) is an autosomal dominant genetic disorder characterized by the growth of benign tumors (hamartomas) throughout multiple organ systems, causing significant neurological, renal, cardiac, pulmonary, and dermatological manifestations that require lifelong multidisciplinary management to reduce morbidity and mortality.
Genetic Basis and Pathophysiology
TSC is caused by mutations in either the TSC1 or TSC2 genes, which encode for hamartin and tuberin proteins respectively. These mutations lead to:
- Disruption of the TSC1-TSC2 intracellular protein complex
- Dysregulation of the mTOR (mammalian target of rapamycin) signaling pathway
- Uncontrolled cell growth and formation of hamartomas in multiple organs 1
Approximately 10-15% of individuals meeting clinical criteria for TSC do not have identifiable mutations in TSC1 or TSC2 1. Two-thirds to three-fourths of TSC cases are due to de novo mutations 1.
Clinical Manifestations by Organ System
Neurological Manifestations
- Subependymal giant cell astrocytomas (SEGAs)
- Cortical tubers and radial migration lines
- Epilepsy (occurs in >60% of patients) 2
- Developmental delay and intellectual disability
- Tuberous-sclerosis-associated neuropsychiatric disorders (TAND) 2
Renal Manifestations
- Angiomyolipomas (AMLs) in 70-80% of patients
- Renal cysts in approximately 50% of patients
- Renal cell carcinoma (3-5% of patients) 1
- Kidney disease is the most common cause of death in adults with TSC 1
Dermatological Manifestations
- Facial angiofibromas
- Hypomelanotic macules ("ash leaf spots")
- Shagreen patches
- Ungual fibromas
Cardiac Manifestations
- Cardiac rhabdomyomas (in approximately two-thirds of newborns with TSC)
- Usually largest during neonatal period and regress with time 1
Pulmonary Manifestations
- Lymphangioleiomyomatosis (LAM), primarily in females
Diagnostic Criteria
Diagnosis is based on clinical criteria established by international consensus. Referral for genetic evaluation should be considered for anyone meeting any two criteria from the major or minor diagnostic criteria lists 1.
Surveillance Recommendations
Brain Monitoring
- Brain MRI every 1-3 years if asymptomatic, until 25 years of age 1
- More frequent monitoring if symptomatic or with growing lesions
Kidney Monitoring
- Blood pressure and GFR measurement annually
- Abdominal ultrasound at diagnosis and every 1-3 years until age 12
- Renal MRI at diagnosis and every 1-3 years starting at age 12 1
- More frequent imaging for tumors approaching 3 cm
Pulmonary Monitoring
- Chest CT at age 18 for females and symptomatic males 1
Cardiac Monitoring
- Echocardiogram at diagnosis, especially if <3 years old
- Repeat if positive until regression 1
Treatment Approaches
mTOR Inhibitors
- Everolimus is FDA-approved for:
- TSC-associated renal angiomyolipomas
- Subependymal giant cell astrocytomas (SEGAs)
- Treatment of adults and children ≥1 year with TSC who have SEGAs that cannot be completely removed by surgery 3
Potential Benefits of Early Treatment
Early mTOR inhibition may prevent the development of TSC lesions and alter the natural history of the disease, as demonstrated in case reports of monozygotic twins where only one received early everolimus treatment 4.
Common Pitfalls in Management
Delayed Diagnosis: TSC is often not recognized in a considerable number of patients due to heterogeneous presentation 5.
Inadequate Surveillance: Normal kidney imaging and GFR in young children do not preclude future development of kidney lesions; all patients require regular monitoring 1.
Inappropriate Surgical Interventions: Many patients with TSC undergo unnecessary surgical procedures or nephrectomies, worsening their risk of chronic kidney disease 1.
Neglect of Neuropsychiatric Manifestations: TAND occurs in most individuals with TSC but is rarely assessed and treated 2.
Poor Transition of Care: Given the age-related expression of manifestations from infancy to adulthood, continuity of clinical care and transition planning from pediatric to adult services is critical 2.
TSC requires coordinated care by a multidisciplinary team of specialists to effectively manage its complex, multisystem manifestations and improve long-term outcomes for patients.