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, intellectual disability / developmental delay, psychiatric illness); kidney (angiomyolipomas, cysts, renal cell carcinomas); heart (rhabdomyomas, arrhythmias); and lungs (lymphangioleiomyomatosis [LAM], multifocal micronodular pneumonocyte hyperplasia). Central nervous system tumors are the leading cause of morbidity and mortality; renal disease is the second leading cause of early death.
Diagnosis/testing: The diagnosis of TSC is established in a proband with one of the following:
Two major clinical features
One major clinical feature and two or more minor features
Identification of a heterozygous pathogenic variant in TSC1 or TSC2 by molecular genetic testing
Management: Treatment of manifestations: For enlarging SEGAs: mTOR inhibitors; neurosurgery when size causes life-threatening neurologic symptoms. For seizures: vigabatrin and other anti-seizure drugs, and on occasion, epilepsy surgery. For renal angiomyolipomas >4 cm, or >3 cm and growing rapidly: mTOR inhibitors are the recommended first line of therapy with secondary therapy options being embolization, renal sparing surgery, or ablative therapy. For facial angiofibromas: topical mTOR inhibitors. For symptomatic cardiac rhabdomyomas: surgical intervention or consideration of mTOR inhibitor therapy. For LAM: mTOR inhibitors. For TSC-associated neuropsychiatric disorder (TAND): refer to a suitable professional to provide appropriate treatment, which may include ABA therapy and consideration of medication for those with ADHD.
Prevention of secondary complications: For those on vigabatrin therapy, vision testing within four weeks of therapy initiation, at three-month intervals while on treatment, and three to six months after treatment is discontinued.
Surveillance: 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 SEGA in childhood should continue to be imaged periodically in adulthood; for those with large or growing SEGA or SEGA causing ventricular enlargement, more frequent brain MRIs as deemed clinically appropriate; screening for TAND at least annually with comprehensive formal evaluation for TAND at key developmental time points; 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; MRI of the abdomen to assess for progression of angiomyolipoma and renal cystic disease every one to three years; assess renal 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; clinical screening for LAM symptoms (exertional dyspnea and shortness of breath) at each clinic visit in women older than age 18 years or those who report respiratory symptoms; high-resolution computed tomography (HRCT) every five to seven years through menopause in asymptomatic individuals at risk for LAM (adult females age >18 years) who have no evidence of lung cysts on baseline HRCT examination;for those with evidence of cystic lung disease consistent with LAM, follow-up scan intervals are determined on a case-by-case basis; annual dermatologic examination; dental examination every six months; annual ophthalmology evaluation.
Agents/circumstances to avoid: Smoking; estrogen use; nephrectomy.
Evaluation of relatives at risk: Identifying affected relatives enables monitoring for early detection of problems associated with TSC, which leads to earlier treatment and better outcomes.
Genetic counseling: TSC is inherited in an autosomal dominant manner. Two thirds of affected individuals have TSC as the result of a de novo pathogenic variant. The offspring of an affected individual are at a 50% risk of inheriting the pathogenic variant. If the pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.
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