What is the treatment approach for a patient with tuberous sclerosis complex (TSC)?

Treatment Approach for Tuberous Sclerosis Complex

All patients with TSC must receive coordinated care from a multidisciplinary team at an expert center, as this approach reduces mortality and morbidity across the multiple organ systems affected by this autosomal dominant disorder. 1, 2

Core Management Framework

Multidisciplinary Team Coordination

• Refer all TSC patients to a specialist center with a multidisciplinary team including neurology, nephrology, pulmonology, dermatology, and other relevant specialties. 1, 2
• Schedule regular follow-up with specialists relevant to the patient's specific manifestations at least annually. 1
• Establish a formal transition plan from pediatric to adult care that specifies the age of transition, process steps, and identification of adult healthcare professionals—this is particularly critical for patients with TSC-associated intellectual disability and neuropsychiatric disorders. 3

Renal Management (Leading Cause of Adult Mortality)

Surveillance Protocol

• Begin kidney surveillance immediately at diagnosis, even in young children, as both cysts and angiomyolipomas can develop within the first months of life. 1, 2
• Perform annual assessment of kidney function and proteinuria in all adults and children with kidney involvement on imaging. 1
• All patients with TSC-associated kidney lesions technically have CKD stage 1 or higher and should be followed by a nephrologist at least annually. 3

Critical pitfall: Normal kidney imaging and GFR in young children do not preclude future development of kidney lesions—lifelong surveillance is mandatory. 2, 4

Angiomyolipoma Management

• For actively bleeding angiomyolipomas that compromise hemodynamics, radiologic intervention is the first-line approach if available (Level X, strong). 1
• Consider preventive arterial embolization for asymptomatic angiomyolipoma >4 cm, especially those with rich angiomatous content. 2
• If embolization fails or is unavailable, partial nephrectomy should be considered. 2
• Emphasize nephron-sparing strategies given the multiplicity and recurrent nature of kidney tumors in TSC. 3

mTOR Inhibitor Therapy

• Everolimus is FDA-approved for treatment of adult patients with TSC-associated renal angiomyolipoma not requiring immediate surgery at 10 mg orally once daily until disease progression or unacceptable toxicity. 5
• mTOR inhibitors are effective in reducing angiomyolipoma size and slowing disease progression. 1
• Monitor for proteinuria development or worsening during mTOR inhibitor therapy. 1, 2

Important caveat: There is a low but increased risk of angioedema when combining mTOR inhibitors with ACE inhibitors—some clinicians prefer angiotensin receptor blockers as first-line in these patients. 3

Renal Cell Carcinoma Management

• No randomized controlled trials support different treatment approaches for TSC-associated RCC compared to sporadic RCC. 3, 1
• TSC-associated RCC has different histopathological patterns and a more indolent course with only rare mortality reports. 3, 1
• Apply nephron-sparing surgical approaches based on multidisciplinary evaluation, with tumor enucleation preferred over marginal resection when malignancy is not suspected. 1

Hypertension Management

Blood Pressure Monitoring

• Perform annual standardized office blood pressure assessment in all children and adults with TSC (Level B, strong). 3
• Use 24-hour ambulatory blood pressure monitoring in children ≥5 years and adults with office BP ≥95th percentile for age/sex/height in children, or ≥120/70 mmHg in adolescents and adults (Level B, moderate). 3
• Patients at high risk (advanced CKD, high-stage angiomyolipoma, or receiving ACTH/steroids for infantile spasms) require frequent blood pressure monitoring. 3

Antihypertensive Treatment

• Use ACE inhibitors or ARBs as first-line treatment for hypertension in TSC patients unless contraindicated (Level B, strong). 3, 1
• Combine with calcium blockers or diuretics if required. 3
• Consider SGLT2 inhibitors for patients with CKD progression, although specific evidence in TSC is limited. 1, 2

Neurological Management

Subependymal Giant Cell Astrocytoma (SEGA)

• Everolimus is FDA-approved for adult and pediatric patients aged ≥1 year with TSC-associated SEGA requiring therapeutic intervention but not curatively resectable. 5
• Starting dosage is 4.5 mg/m² orally once daily. 5
• Perform therapeutic drug monitoring to maintain whole blood trough concentrations of 5-15 ng/mL, assessing levels 1-2 weeks after initiation or dose modification. 5
• Monitor with brain MRI every 1-3 years until age 25. 4

Epilepsy Management

• Monitor for and treat epilepsy aggressively, as it is a leading cause of mortality in TSC patients. 2, 4

Post-Kidney Transplant Management

• Do not perform routine nephrectomy in TSC patients who have undergone kidney transplant (Level X, strong). 1
• Consider mTOR inhibitor-based immunosuppressive regimens for TSC patients with known responsiveness to mTOR inhibition after kidney transplant. 1, 2

Family Screening and Genetic Counseling

• Discuss genetic screening with family members who have TSC clinical features—screen for the relevant pathogenic variant if known. 3, 2
• Genetic testing has limited value in family members with no clinical features of TSC. 3, 2
• Pre-implantation genetic diagnosis is possible if a mosaic or heterozygous pathogenic variant has been identified. 3

Critical Monitoring Pitfalls

• In patients with low muscle mass due to severe neurological complications, standard creatinine-based equations overestimate eGFR—use cystatin C-based equations instead. 2
• TSC is often not recognized by clinicians without specialist knowledge, as <40% of patients have the classic triad of facial angiofibromata, developmental delay, and intractable epilepsy. 2, 4
• During interventional procedures, ensure effective targeting of angiomatous arteries and avoid non-target embolization to prevent unnecessary nephron loss. 2