How should a newborn diagnosed with tuberous sclerosis complex be evaluated and managed, including genetic testing, baseline brain MRI, cardiac echocardiogram, renal ultrasound, ophthalmologic exam, seizure treatment with vigabatrin, therapy for symptomatic cardiac rhabdomyomas, renal lesion surveillance, dermatologic care, parental counseling, and follow‑up schedule?

Management of Tuberous Sclerosis Complex in a Neonate

A newborn diagnosed with tuberous sclerosis complex requires immediate multidisciplinary evaluation including genetic testing, baseline brain MRI, cardiac echocardiogram, renal ultrasound, dilated ophthalmologic exam, and presymptomatic EEG monitoring with vigabatrin initiation if subclinical seizures are detected, as early intervention before seizure onset can significantly improve neurodevelopmental outcomes.

Initial Diagnostic Workup at Birth

Genetic Testing

• Confirm the diagnosis through genetic testing for TSC1 and TSC2 mutations immediately, as this provides definitive diagnosis and informs family planning 1
• Genetic testing should be performed for all patients with definite or suspected TSC 1
• High-sensitivity genetic analysis is recommended if standard testing is negative, as mosaicism can be present at allele frequencies as low as 1-2% 1
• Important caveat: 10-15% of patients meeting clinical criteria have no identifiable mutation due to mosaicism, so negative genetic testing does not exclude TSC 1

Neurological Evaluation

• Obtain noncontrast brain MRI at diagnosis to assess for cortical tubers, subependymal nodules, and subependymal giant cell astrocytomas (SEGAs) 1, 2
• Cortical dysplasias including radial migration lines and multiple cortical tubers are major diagnostic features, present in 94% of infants 1, 3
• Perform presymptomatic EEG monitoring immediately, even before clinical seizures appear 4
• This is critical because subclinical status epilepticus can occur on day 1 of life and contribute to developmental delays 4
• Only 15% of infants present with seizures initially, but 73% develop epilepsy within the first year 3

Cardiac Assessment

• Perform echocardiogram at diagnosis, especially critical in neonates as approximately two-thirds have cardiac rhabdomyomas 1, 2
• Cardiac rhabdomyomas are the most common initial presenting feature (59% of cases) and are largest during the neonatal period 1, 3
• These tumors typically regress spontaneously over time with 100% survival rate and no long-term cardiac dysfunction 5
• Follow-up echocardiograms should be performed every 1-3 years until regression is documented 2

Renal Evaluation

• Obtain baseline renal ultrasound at diagnosis, as both cysts and angiomyolipomata can develop in the first months of life 1, 2
• The median age for detection of cysts is 3 years and angiomyolipomata is 8-13 years, but both can appear in early infancy 1
• Perform abdominal ultrasound every 1-3 years until age 12, then transition to MRI every 1-3 years 1, 2
• Kidney disease is the most common cause of death in adults with TSC, making early surveillance essential 1, 2

Ophthalmologic Examination

• Perform annual dilated fundoscopic examination to detect retinal hamartomas, which are present in 87% of individuals with TSC 1, 2
• These lesions may be difficult to detect without pupil dilation and indirect ophthalmoscopy 1

Dermatologic Assessment

• Conduct thorough skin examination for hypomelanotic macules, which are present in 94% of infants and are the second most common presenting feature (39% at initial presentation) 3
• Skin lesions occur in nearly 100% of individuals with TSC, though none are pathognomonic 1
• Hypomelanotic macules are often the earliest visible sign and can be present at birth 3, 6

Seizure Management

Vigabatrin Therapy

• Initiate vigabatrin immediately if subclinical seizures or ictal discharges are detected on EEG, even without clinical manifestations 4, 6
• The EPISTOP and PREVeNT trials demonstrated that early life initiation of vigabatrin reduces the degree of refractory epilepsy and epileptic spasms in TSC 4
• Start vigabatrin before the typical seizure onset window (4th-6th months of life) to potentially improve neurodevelopmental outcomes 6
• Early treatment of subclinical status epilepticus may prevent developmental delays 4

EEG Monitoring Schedule

• Begin EEG monitoring presymptomatically in the neonatal period, as neonatal seizures are a known entity in TSC 4
• Continue regular EEG surveillance even if initial studies are normal, as seizure onset typically occurs between 4-6 months of age 6

Management of Cardiac Rhabdomyomas

Symptomatic Treatment

• Most cardiac rhabdomyomas require only observation, as they spontaneously regress in 47% of cases with no long-term cardiac dysfunction 5
• Intervention is rarely needed unless tumors cause hemodynamic compromise or arrhythmias 5
• Monitor with serial echocardiograms every 1-3 years until documented regression 2

Blood Pressure and Renal Function Monitoring

Initial Assessment

• Perform baseline blood pressure measurement, kidney function assessment (creatinine or cystatin C), and proteinuria screening at diagnosis 7
• In neonates with low muscle mass, standard creatinine-based eGFR equations can overestimate kidney function; consider cystatin C-based measurements 7, 2

Ongoing Surveillance

• Annual standardized office blood pressure measurements for all patients 7, 2
• In children without kidney involvement on imaging, less frequent blood tests (or delayed until adulthood) are acceptable 7
• In children with kidney involvement on imaging, perform annual blood tests to assess kidney function and proteinuria 7
• If blood pressure ≥95th percentile in children, perform 24-hour ambulatory blood pressure monitoring 7

Special Considerations

• Children with TSC and kidney cysts may develop polyuria due to urine-concentrating defects, placing them at risk of nocturnal enuresis 7
• Avoid vasopressin analogues (desmopressin) in children with TSC and kidney cysts 7
• If TSC2-PKD1 contiguous gene syndrome is identified, perform more frequent monitoring of blood pressure and kidney function due to high risk of early kidney involvement 7

Parental Counseling

Genetic Counseling

• Discuss that two-thirds to three-fourths of TSC cases are de novo mutations 1
• Parents of a child with seemingly sporadic TSC have a 1-2% risk of having another affected child due to possible germline mosaicism 1, 8
• Recommend genetic screening for family members with TSC clinical features 7, 8, 2
• Genetic testing has limited value in family members with no clinical features 7, 2

Disease Education

• Explain that TSC2 mutations generally cause more severe disease than TSC1 mutations, particularly regarding neurological manifestations and kidney involvement 1
• Emphasize that normal kidney imaging in infancy does not exclude future development of renal lesions, as angiomyolipomata and cysts can develop at any time 1, 2
• Counsel that epilepsy is a leading cause of mortality in TSC patients, affecting approximately 82% 8

Prognosis Discussion

• Inform parents that less than 40% of patients have the classic triad of facial angiofibromata, developmental delay, and intractable epilepsy, so the clinical presentation is highly variable 1, 2
• Discuss that molecular characterization of TSC1 and TSC2 might be helpful in predicting neurodevelopmental outcomes, as 75% of infants with identified mutations showed neurologic impairment in one study 5

Multidisciplinary Care Coordination

Referral to Specialized Center

• Refer immediately to a TSC specialty center with multidisciplinary expertise including neurology, nephrology, cardiology, dermatology, and ophthalmology 7, 1, 8, 2
• TSC is often not recognized by clinicians without specialist knowledge 1, 2
• All patients with TSC-associated kidney lesions should be followed by a nephrologist at least annually 7

Care Team Structure

• Coordinate structured follow-up visits at least annually, ideally with multiple specialists on the same day 8, 2
• Establish a transition plan from pediatric to adult care early, including specified age of transition, process steps, and identification of adult healthcare professionals 7, 8, 2

Follow-Up Schedule

Neurological Surveillance

• Brain MRI every 1-3 years until age 25 to monitor for SEGA development 1, 2
• Regular neurological monitoring for seizures and developmental issues 1
• Continue EEG monitoring as clinically indicated based on seizure activity 4

Renal Surveillance

• Abdominal ultrasound every 1-3 years until age 12 1, 2
• Transition to MRI every 1-3 years after age 12 1, 2
• Annual kidney function assessment and proteinuria screening in patients with kidney involvement on imaging 7, 2

Cardiac Surveillance

• Echocardiogram every 1-3 years until regression of cardiac rhabdomyomas 2

Ophthalmologic Surveillance

• Annual dilated fundoscopic examination 1, 2

Blood Pressure Monitoring

• Annual standardized office blood pressure measurements 7, 2

Critical Pitfalls to Avoid

• Do not assume normal kidney imaging in neonates excludes future kidney disease—lesions can develop at any time throughout life 1, 8, 2
• Do not delay EEG monitoring until clinical seizures appear—subclinical status epilepticus can occur from day 1 and contribute to developmental delays 4
• Do not use standard creatinine-based eGFR equations in neonates with low muscle mass—they overestimate kidney function; use cystatin C-based measurements instead 7, 2
• Do not prescribe desmopressin for nocturnal enuresis in children with TSC and kidney cysts—it may worsen cyst progression 7
• Do not delay referral to a specialized TSC center—early multidisciplinary management is essential for optimal outcomes 7, 1, 8, 2
• Do not assume negative genetic testing excludes TSC—10-15% of patients meeting clinical criteria have no identifiable mutation due to mosaicism 1