What is the cause, pathophysiology, differential diagnosis, symptoms, diagnosis, and treatment with dosage guidelines for Tuberous Sclerosis Complex (TSC)?

Tuberous Sclerosis Complex: Cause, Pathophysiology, Diagnosis, and Treatment

Tuberous Sclerosis Complex (TSC) is a genetic disorder caused by mutations in TSC1 or TSC2 genes that leads to hamartomatous lesions in multiple organ systems, requiring a multidisciplinary approach for diagnosis and management to reduce morbidity and mortality. 1

Cause and Pathophysiology

• TSC is an autosomal dominant disorder with a birth incidence of approximately 1 in 5,800, affecting over one million patients worldwide 1
• Caused by mutations in tumor suppressor genes TSC1 (chromosome 9q34) and TSC2 (chromosome 16p13) that inactivate their tumor-suppressive function 1
• Two-thirds to three-fourths of cases have de novo mutations rather than inherited patterns 1
• TSC2 mutations generally cause more severe disease than TSC1 mutations, particularly regarding neurological manifestations and kidney involvement 1
• The mutated genes lead to dysregulation of the mammalian target of rapamycin (mTOR) pathway, resulting in abnormal cell growth and proliferation of hamartomas in multiple organs 1, 2
• Combined deletion of TSC2 and PKD1 genes results in an accelerated cystic kidney disease phenotype 1

Differential Diagnosis

• Neurofibromatosis type 1 (similar skin manifestations but different types of tumors) 1
• Polycystic kidney disease (can be confused with TSC renal manifestations) 1
• Isolated cardiac rhabdomyomas (can be the only initial manifestation of TSC) 1
• Isolated seizure disorders without other manifestations 1
• Sporadic lymphangioleiomyomatosis (can occur without other TSC features) 1
• Focal cortical dysplasia (can mimic cortical tubers on imaging) 1

Clinical Manifestations and Diagnosis

Major Organ System Involvement

• Neurological manifestations:

  • Brain lesions include subependymal nodules, cortical hamartomas (tubers), areas of focal cortical hypoplasia, and heterotopic gray matter 1
  • Epilepsy is a leading cause of mortality in TSC patients 1
  • 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
  • Three major kidney phenotypes: angiomyolipomata (70-80% of patients), cystic kidney disease (approximately 50%), and renal cell carcinoma (3-5%) 1
  • Approximately 40% of adult patients have low glomerular filtration rate 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

• Skin manifestations:

  • Skin lesions occur in nearly 100% of individuals with TSC 1
  • Include facial angiofibromata, hypomelanotic macules, shagreen patches, and ungual fibromas 1, 3

• Ocular manifestations:

  • Retinal lesions are present in 87% of individuals with TSC 1
  • 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

• Major diagnostic criteria include:

  • Cortical dysplasias (including radial migration lines and multiple cortical tubers) 1
  • Hypomelanotic macules (≥3, at least 5mm diameter) 1, 3
  • Facial angiofibromas (≥3) or fibrous cephalic plaque 1, 3
  • Ungual fibromas (≥2) 1, 3
  • Shagreen patch 1, 3
  • Multiple retinal hamartomas 1
  • Subependymal nodules 1
  • Subependymal giant cell astrocytoma 1
  • Cardiac rhabdomyoma 1
  • Lymphangioleiomyomatosis 1
  • Angiomyolipomas (≥2) 1

• Genetic testing is recommended for all patients with definite or suspected TSC 1

• High-sensitivity genetic analysis is recommended if standard testing is negative, as mosaicism is common 1

• 10-15% of patients meeting clinical criteria for TSC have no identifiable mutation in TSC1 or TSC2 genes 1

Treatment with Dosage Guidelines

General Management Approach

• A coordinated multidisciplinary approach involving specialists from neurology, nephrology, pulmonology, dermatology, and other disciplines is essential 4
• All patients with TSC should be referred to an expert center with a multidisciplinary team 4
• Regular follow-up should occur at least annually with relevant specialists 4

Specific Treatments

mTOR Inhibitors

• Everolimus for TSC-Associated Renal Angiomyolipoma:

  • Recommended dosage: 10 mg orally once daily until disease progression or unacceptable toxicity 5
  • First-line pharmacological treatment for angiomyolipomas ≥3 cm 1, 4

• Everolimus for TSC-Associated Subependymal Giant Cell Astrocytoma (SEGA):

  • Recommended starting dosage: 4.5 mg/m² orally once daily 5
  • Titrate dose to attain trough concentrations of 5-15 ng/mL 5
  • Monitor everolimus whole blood trough concentrations 1-2 weeks after initiation 5

• Dosage Modifications for Adverse Reactions:

  • For Grade 2 non-infectious pneumonitis: Withhold until improvement to Grade 0-1, then resume at 50% of previous dose 5
  • For Grade 3 stomatitis: Withhold until improvement to Grade 0-1, then resume at 50% of previous dose 5
  • For Grade 3 metabolic events (hyperglycemia, dyslipidemia): Withhold until improvement to Grade 0-2, then resume at 50% of previous dose 5

Hypertension Management

• Annual standardized office blood pressure assessment in all patients with TSC 6
• 24-hour ambulatory blood pressure monitoring in those with office blood pressure ≥95th percentile for age, sex and height in children, or ≥120/70mmHg in adolescents and adults 6
• First-line treatment: ACE inhibitors or angiotensin receptor blockers 6
• For patients receiving mTORC1 inhibitors, angiotensin receptor blockers may be preferable to ACE inhibitors due to risk of angioedema 6

Renal Management

• Begin kidney monitoring from diagnosis, even in young children 1, 4
• For angiomyolipomata, consider arterial embolization as first-line approach for actively bleeding lesions 4
• Consider preventive arterial embolization for asymptomatic angiomyolipoma >4 cm 4
• Partial nephrectomy should be considered when embolization fails or is unavailable 4

Monitoring Recommendations

• Brain MRI every 1-3 years until age 25 to monitor for SEGA 1
• Renal imaging: Abdominal ultrasound every 1-3 years until age 12, then transition to MRI every 1-3 years 1
• Annual assessment of kidney function and proteinuria in adults and children with kidney involvement 1, 4
• Chest CT at age 18 for females and symptomatic males to screen for lymphangioleiomyomatosis 1

Common Pitfalls and Caveats

• TSC is often not recognized by clinicians without specialist knowledge, as <40% of patients have the classic triad 1, 4
• Normal kidney imaging and GFR in young children do not preclude future development of kidney lesions 4
• In patients with low muscle mass due to severe neurological complications, standard creatinine-based equations can overestimate eGFR; consider cystatin C-based equations 4
• Avoid nephron loss during interventional procedures by ensuring effective targeting of angiomatous arteries 4
• Parents of a child with seemingly sporadic TSC have a 1-2% risk of having another affected child due to possible germline mosaicism 1