Tuberous Sclerosis Complex

Clinical characteristics: Tuberous sclerosis complex (TSC) involves abnormalities of the skin (hypomelanotic macules, confetti skin lesions, facial angiofibromas, shagreen patches, fibrous cephalic plaques, ungual fibromas); brain (subependymal nodules, cortical tubers, and subependymal giant cell astrocytomas [SEGAs], seizures, TSC-associated neuropsychiatric disorder [TAND]); kidneys (benign renal angiomyolipomas, epithelial cysts, oncocytoma, renal cell carcinoma); heart (rhabdomyomas, arrhythmias); and lungs (lymphangioleiomyomatosis [LAM], multifocal micronodular pneumonocyte hyperplasia). Central nervous system-related problems (including TAND) are the leading cause of morbidity, whereas kidney disease is the leading cause of mortality.

Diagnosis/testing: The clinical diagnosis of TSC can be established in a proband based on clinical diagnostic criteria (presence of two major clinical features or one major clinical feature and two or more minor features). The molecular diagnosis can be established in a proband with a heterozygous pathogenic variant in TSC1 or TSC2 identified by molecular genetic testing.

Management: Targeted therapies: Treatment with an mTOR inhibitor for enlarging SEGAs, intractable epilepsy, renal angiomyolipomas that are >4 cm, rapidly growing renal angiomyolipomas that are >3 cm, and LAM. Topical mTOR inhibitors for facial angiofibromas.

Treatment of manifestations: Neurosurgery for enlarging SEGAs that are causing life-threatening neurologic symptoms. Seizure treatments include vigabatrin, other anti-seizure medications, dietary therapy, and epilepsy surgery. Referral to a neurodevelopmental specialist and/or psychiatrist for TAND; applied behavior analysis for autism spectrum disorder; consideration of medication for those with attention-deficit/hyperactivity disorder. Treatment of renal cysts per nephrologist and surgical specialists. Secondary therapy options for renal angiomyolipomas that are >4 cm or rapidly growing renal angiomyolipomas that are >3 cm include selective embolization followed by corticosteroids, kidney-sparing resection, or ablative therapy. Embolization followed by corticosteroids for renal angiomyolipomas with acute hemorrhage. Treatment of retinal astrocytic hamartoma per ophthalmologist; treatment of extrarenal angiomyolipomas per surgeon and/or oncologist; treatment of neuroendocrine tumors per endocrinologist, surgeon, and/or oncologist.

Surveillance: Detailed annual dermatologic examination. Brain MRI every one to three years in asymptomatic individuals with TSC younger than age 25 years to monitor for new occurrence of SEGAs; those with asymptomatic SEGAs in childhood should continue to be imaged periodically in adulthood; for those with large or growing SEGAs or SEGA-causing ventricular enlargement, more frequent brain MRIs as deemed clinically appropriate. Assessment with neurologist for manifestations of seizures at each visit; EEG in asymptomatic infants every six weeks up to age 12 months, every three months up to age 24 months, and in individuals with known or suspected seizure activity as clinically indicated; prolonged video EEG in those with suspected seizures and normal routine EEG. Screening for TAND at least annually with comprehensive formal evaluation for TAND at key developmental time points. Abdominal MRI to assess for new or progression of angiomyolipoma and cystic kidney disease every one to three years; assess kidney function (glomerular filtration rate and blood pressure) at least annually. Echocardiogram every one to three years in asymptomatic infants and children with cardiac rhabdomyomas until regression is documented; echocardiogram in those with symptomatic cardiac rhabdomyomas per cardiologist. Clinical screening for LAM symptoms (exertional dyspnea and shortness of breath) at each visit in females older than age 18 years and males and females with respiratory symptoms; high-resolution CT every five to seven years in asymptomatic females without lung cysts beginning after age 18 years and continuing through menopause; for those with LAM-related cystic lung disease on CT, follow-up scan intervals are determined on an individual basis. Annual ophthalmology evaluation; vision testing for those on vigabatrin therapy. Surveillance for neuroendocrine tumors per endocrinologist. Detailed dental examination every six months with panoramic radiographs by age seven years.

Agents/circumstances to avoid: Smoking; estrogen use; nephrectomy.

Evaluation of relatives at risk: It is appropriate to evaluate apparently asymptomatic older and younger at-risk relatives (including children) of an affected individual in order to identify as early as possible those who would benefit from surveillance and early treatment.

Pregnancy management: Discussion of the risks and benefits of using a given anti-seizure medication during pregnancy should ideally take place prior to conception.

Genetic counseling: TSC is inherited in an autosomal dominant manner. About one third of individuals diagnosed with TSC have an affected parent; two thirds of individuals with TSC have the disorder as the result of a de novo pathogenic variant. Each child of an individual with TSC has a 50% chance of inheriting the TSC-related pathogenic variant. If the TSC-related pathogenic variant has been identified in an affected family member, predictive testing for at-risk asymptomatic family members and prenatal/preimplantation genetic testing is possible.