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

Management of Twins with Tuberous Sclerosis Complex

Twins with tuberous sclerosis complex (TSC) require coordinated multidisciplinary care from diagnosis through adulthood, with each twin managed individually according to their specific organ involvement, as TSC manifestations vary significantly even between identical twins. 1, 2

Initial Diagnostic Approach

• Establish TSC diagnosis in each twin independently using genetic testing for TSC1 or TSC2 mutations, as clinical manifestations can differ substantially between twins despite shared genetics 3, 4
• Perform comprehensive baseline evaluation for both twins at diagnosis, including brain MRI, renal imaging (ultrasound or MRI), echocardiography, and dermatologic examination 1, 3
• Begin surveillance immediately upon diagnosis, even in asymptomatic infants, as renal cysts and angiomyolipomas can develop within the first months of life 2, 3

Multidisciplinary Team Structure

Both twins must be referred to a specialized TSC center with coordinated care across neurology, nephrology, pulmonology, dermatology, and cardiology. 1, 2 This is critical because:

• TSC affects multiple organ systems with variable penetrance between individuals 4, 5
• Kidney disease is the leading cause of death in adults with TSC 2, 3
• Epilepsy and neurological complications are major contributors to mortality across all ages 2, 3

Neurological Management for Each Twin

• Monitor both twins for seizure onset with low threshold for EEG evaluation, as early seizure detection and treatment (particularly with vigabatrin for infantile spasms) improves neurodevelopmental outcomes 6
• Children diagnosed before seizure onset have significantly better developmental outcomes and less severe epilepsy compared to those diagnosed after seizures begin 6
• Severe developmental disability most commonly occurs when first seizures present before 12 months of age 6

Renal Surveillance Protocol

Initiate kidney monitoring at diagnosis for both twins, regardless of age, and continue throughout life: 7, 2, 3

• Perform renal imaging (MRI preferred over ultrasound for characterization) at diagnosis, then annually or more frequently based on findings 7, 2
• Monitor for three distinct phenotypes: angiomyolipomas (70-80% prevalence), cystic disease (~50%), and renal cell carcinoma (3-5%) 2
• Measure blood pressure annually with standardized office measurements 2, 3
• In adults with BP ≥120/70 mmHg, perform 24-hour ambulatory blood pressure monitoring 2, 3
• Assess kidney function (GFR) and proteinuria annually in all adults and in children with renal involvement on imaging 7, 2, 3

Critical caveat: Normal kidney imaging and GFR in young children does not preclude future development of kidney lesions, so surveillance must continue indefinitely 2, 3

Management of Renal Angiomyolipomas

For angiomyolipomas >3 cm or those causing symptoms: 1, 2

• Consider mTOR inhibitor therapy (everolimus 10 mg daily) for asymptomatic angiomyolipomas ≥3 cm not requiring immediate surgery 8
• For actively bleeding angiomyolipomas compromising hemodynamics, perform arterial embolization as first-line intervention 1, 3
• Consider preventive arterial embolization for asymptomatic angiomyolipomas >4 cm, especially those with rich angiomatous content 2, 3
• Use nephron-sparing surgical approaches if embolization fails or is unavailable 3

mTOR Inhibitor Therapy Considerations

Everolimus is FDA-approved for TSC-associated renal angiomyolipomas and subependymal giant cell astrocytomas (SEGA) in patients ≥1 year old: 8

• Standard dosing for angiomyolipomas: 10 mg orally once daily until disease progression or unacceptable toxicity 8
• For SEGA: Start at 4.5 mg/m² daily with therapeutic drug monitoring targeting trough concentrations of 5-15 ng/mL 8
• Monitor for proteinuria before starting and regularly during treatment, as mTOR inhibitors can cause or worsen proteinuria 7, 2, 3
• Assess trough concentrations 1-2 weeks after initiation or dose modification 8

Hypertension Management

Use ACE inhibitors or ARBs as first-line antihypertensive therapy in both twins: 1, 2, 3

• These agents are preferred based on their renoprotective effects 2, 3
• Consider SGLT2 inhibitors for twins with progressive chronic kidney disease, though specific TSC evidence is limited 1, 2, 3

Cardiac Evaluation

• Perform echocardiography at diagnosis to screen for cardiac rhabdomyomas, which can cause heart failure in neonates 5
• Cardiac rhabdomyomas typically regress spontaneously but require monitoring 5

Surveillance Schedule

Establish individualized surveillance for each twin based on their specific manifestations: 1, 2, 3

• Annual follow-up with all relevant specialists (minimum) 1, 3
• Renal imaging and function assessment annually 7, 2
• Blood pressure monitoring annually 2, 3
• Neurological assessment frequency based on seizure control and developmental concerns 6
• Every 3-6 months for stable patients on mTOR inhibitors with changing body surface area 8

Transition Planning

• Establish a formal transition plan from pediatric to adult care, specifying the age of transition, process steps, and identification of adult healthcare providers 3
• This is particularly important for twins as they may have different manifestation severity requiring different transition timelines 3

Genetic Counseling and Family Screening

• Discuss genetic screening with other family members, as TSC is autosomal dominant with variable penetrance 3, 9
• Screen family members with TSC clinical features for the identified pathogenic variant 3
• Note that two-thirds of TSC cases represent sporadic mutations, so negative family history does not exclude diagnosis 9

Critical Pitfalls to Avoid

• Do not assume both twins will have identical disease progression – TSC has extreme phenotypic variability even between identical twins 4, 5
• Do not defer kidney function monitoring in children with normal imaging, as approximately 40% of adults with TSC develop low GFR 2
• In twins with severe neurological complications and low muscle mass, use cystatin C-based equations rather than creatinine-based equations for more accurate GFR estimation 7, 3
• Do not delay referral to specialized TSC center – fewer than 40% of patients present with the classic triad of facial angiofibromas, developmental delay, and intractable epilepsy 3