What is the management plan for tuberous sclerosis complex (TSC)?

Management of Tuberous Sclerosis Complex

Multidisciplinary Care Coordination

All patients with TSC must be referred to a specialized expert center with a multidisciplinary team that includes neurology, nephrology, pulmonology, dermatology, and cardiology. 1, 2, 3 This coordinated approach is essential because TSC affects multiple organ systems and is the primary strategy to reduce morbidity and mortality. 2, 3

• Structured follow-up visits should occur at least annually, ideally coordinating multiple specialists on the same day to improve care efficiency. 1, 2
• Establish a formal transition plan from pediatric to adult care services, specifying the age of transition and identifying adult healthcare professionals. 1, 3

Common pitfall: TSC is frequently not recognized by clinicians without specialist knowledge, as less than 40% of patients present with the classic triad of facial angiofibromas, developmental delay, and intractable epilepsy. 3, 4

Initial Diagnostic Assessment

At the time of TSC diagnosis, perform a comprehensive baseline evaluation: 1

• Complete clinical history
• Kidney or abdominal imaging (MRI preferred)
• Assessment of kidney function (eGFR) and proteinuria
• Blood pressure measurement
• Brain MRI to evaluate for cortical tubers and subependymal nodules

Renal Management

Surveillance Protocol

Begin kidney monitoring immediately at diagnosis, even in infants, as both cysts and angiomyolipomas can develop in the first months of life. 1, 2, 3 Kidney disease is the most common cause of death in adults with TSC. 2, 3

• MRI is the preferred imaging modality for detecting and monitoring kidney lesions in both children and adults. 1
• In children, ultrasound performed by an expert radiologist who routinely images kidney tumors is an acceptable alternative. 1
• In adults, contrast-enhanced CT is an acceptable alternative to MRI. 1
• Imaging follow-up should occur at intervals of 1-3 years, with frequency adjusted based on the presence and type of kidney lesions and bleeding risk factors. 1
• Use the same imaging modality consistently when assessing growth of kidney masses to ensure accurate comparison. 1

Kidney Function Monitoring

• In adults with TSC, perform annual blood and urine tests to monitor kidney function and urinary protein excretion. 1
• In children with TSC and kidney involvement on imaging, perform at least annual assessment including pain evaluation, clinical bleeding risk assessment, blood pressure, and biochemical kidney function tests. 1
• In children without kidney involvement on imaging, less frequent blood tests or deferral until adulthood is acceptable. 1
• In patients with low muscle mass due to severe neurological complications, use cystatin C-based eGFR measurements rather than standard creatinine-based equations, which can overestimate kidney function. 1, 3

Angiomyolipoma Management

For actively bleeding angiomyolipomas that compromise hemodynamics, radiologic intervention (arterial embolization) is the first-line approach if available. 2, 3

• Consider preventive arterial embolization for asymptomatic angiomyolipomas >4 cm, especially those with rich angiomatous content. 3
• Partial nephrectomy should be considered when embolization fails or is unavailable. 3
• For TSC-associated angiomyolipomas, everolimus 10 mg orally once daily is FDA-approved and effective in reducing tumor size. 5 mTOR inhibitors are effective in reducing angiomyolipoma size and slowing disease progression. 2

Critical monitoring during mTOR inhibitor therapy:

• Assess eGFR and proteinuria before starting treatment. 1
• Monitor eGFR and proteinuria every 3-12 months during treatment, as proteinuria may develop or worsen. 1, 2, 3

Renal Cell Carcinoma Management

• TSC-associated RCC has different histopathological patterns and a more indolent course than sporadic RCC, with only rare mortality reports. 1, 2
• A nephron-sparing surgical approach is strongly recommended for TSC-associated RCC based on multidisciplinary evaluation. 2
• For cases without suspicion of malignancy, tumor enucleation is preferred over marginal tumor resection. 2
• No randomized controlled trials support different treatment approaches for TSC-associated RCC compared to sporadic RCC, so general RCC management principles apply. 1, 2

Kidney Transplantation Considerations

• Routine nephrectomy in TSC patients undergoing kidney transplantation should be avoided. 1, 2 The weak retrospective evidence does not support routine nephrectomy given the 1.4-2.8% major complication rate and blood transfusion rates as high as 9.1%. 1
• Consider nephrectomy on a case-by-case basis only for suspected kidney malignancy or angiomyolipoma with high bleeding risk that cannot be treated with mTOR inhibitors. 1
• After kidney transplantation, consider mTOR inhibitor-based immunosuppressive regimens in TSC patients with known responsiveness to mTOR inhibition. 2, 3 This addresses concerns about future bleeding events. 1

Blood Pressure Management

Hypertension diagnosis and monitoring should be conducted by a nephrologist with consideration of primary and secondary etiologies. 1

• Perform annual standardized office blood pressure measurements for all patients. 1, 2, 3
• Conduct 24-hour ambulatory blood pressure monitoring if BP ≥120/70 mmHg in adults or ≥95th percentile in children. 1
• ACE inhibitors or ARBs are first-line treatment for hypertension in TSC patients. 1, 2, 3
• Consider SGLT2 inhibitors for patients with CKD progression, although specific evidence in the TSC population is limited. 2, 3
• Provide general lifestyle advice: avoid smoking, maintain healthy BMI, avoid NSAIDs. 1

Special monitoring situations:

• In infants and young children receiving adrenocorticotropic hormone and corticosteroids, monitor blood pressure more frequently than annually, as hypertension risk increases up to 44%. 1
• Monitor blood pressure as part of pre-anesthesia assessment when patients undergo general anesthesia. 1
• After bleeding episodes and embolization procedures, monitor kidney function more frequently until it stabilizes. 1

Neurological Management

• Monitor for and treat epilepsy, which is a leading cause of mortality in TSC and occurs in approximately 82% of patients. 3, 6
• Obtain brain MRI every 1-3 years until age 25 to monitor for subependymal giant cell astrocytomas (SEGA). 6

SEGA Management

For TSC-associated SEGA requiring therapeutic intervention but not curatively resectable, everolimus is FDA-approved starting at 4.5 mg/m² orally once daily. 5

• Therapeutic drug monitoring is essential for SEGA treatment: Titrate dose to attain whole blood trough concentrations of 5-15 ng/mL. 5
• Assess trough concentrations 1-2 weeks after initiation, dose modification, or changes in concomitant medications affecting drug metabolism. 5
• For stable doses with stable body surface area, monitor trough concentrations every 6-12 months. 5

Cardiac Management

• Approximately two-thirds of newborns with TSC have cardiac rhabdomyomas, which are largest during the neonatal period and typically regress with time. 6
• Perform baseline cardiac evaluation at diagnosis. 6

Pulmonary Management

• Pulmonary involvement (lymphangioleiomyomatosis) occurs predominantly in women and carries high morbidity and mortality. 7
• Include pulmonary specialists in the multidisciplinary team for appropriate surveillance. 2, 3

Genetic Counseling and Family Screening

• Discuss genetic screening with family members. 2, 3
• Family members with TSC clinical features should be screened for the relevant pathogenic variant if known. 2, 3
• Genetic testing has limited value in family members with no clinical features of TSC. 3
• Parents of seemingly sporadic TSC cases have a 1-2% risk of having another affected child due to possible germline mosaicism. 6

Special Populations

TSC2-PKD1 Contiguous Gene Syndrome

• Perform more frequent monitoring of blood pressure and kidney function given the associated high risk of early kidney involvement and complications. 1
• Conduct full clinical, biochemical, and radiological assessment of kidney involvement at diagnosis. 1

Children with Kidney Cysts and Nocturnal Enuresis

• Avoid vasopressin analogues (such as desmopressin) in children with TSC and kidney cysts who have nocturnal enuresis. 1 This is due to the theoretical risk of kidney cyst progression and the presence of a urine-concentrating defect causing polyuria. 1

Critical Pitfalls to Avoid

• Do not assume normal kidney imaging in young children excludes future kidney disease—lesions can develop at any time throughout life. 2, 3, 6
• Do not delay referral to specialized centers—early multidisciplinary involvement is crucial for optimal outcomes. 2, 3
• Do not use different imaging modalities interchangeably when tracking lesion growth—this leads to inaccurate assessments. 1
• Do not routinely perform nephrectomy before kidney transplantation—the risks often outweigh benefits. 1, 2