Tuberous sclerosis complex

Updated March 21, 2025

Background

Overview

Definition

TSC is a genetic neurocutaneous disorder affecting multiple organs including skin, brain, kidneys, heart, and lungs.

Pathophysiology

The pathophysiology of TSC is linked to mutations in the TSC1 and TSC2 genes, encoding hamartin and tuberin proteins that regulate the protein kinase B/mTOR signaling pathway. Mutations in these genes lead to dysregulation of the mTOR pathway, resulting in abnormal cell growth and the formation of hamartomas in multiple organ systems. Autosomal dominant inheritance is reported in about one-third of cases.

Epidemiology

The incidence of TSC is estimated at 1 per 5,800-10,000 live births.

Risk factors

The main risk factor for TSC is the family history of the condition; however, spontaneous mutations are also common. Some patients may have concomitant autosomal dominant polycystic kidney disease as a result of a contiguous gene deletion involving TSC2 and PDK1.

Disease course

The clinical course of TSC is highly variable involving multiple organ systems (brain, skin, heart, lungs, and kidneys), with symptoms ranging from mild to severe and often not appearing until later in life. Most features of TSC become evident only in childhood after 3 years of age. Cutaneous manifestations include hypopigmented macules, facial angiofibromas, fibrous cephalic plaques, and ungual fibromas. Neurological manifestations include seizures, cognitive dysfunction, and autism spectrum disorder. Renal manifestations include renal angiomyolipomas, renal epithelial cysts, and renal cell carcinoma. Pulmonary manifestations include pulmonary lymphangioleiomyomatosis and multifocal micronodular pneumocyte hyperplasia. Cardiovascular manifestations include cardiac rhabdomyomas and cardiac arrhythmias. Retinal manifestations include retinal hamartomas and retinal achromic patches.

Prognosis and risk of recurrence

The prognosis of TSC is worse in cases with CNS and renal tumors.

Guidelines

Key sources

The following summarized guidelines for the evaluation and management of tuberous sclerosis complex are prepared by our editorial team based on guidelines from the Japanese Respiratory Society (JRS/ATS 2016), the Tuberous Sclerosis Complex International (TSCi 2013), and the European Respiratory Society (ERS 2010).

Screening and diagnosis

Screening of family relatives

As per TSCi 2013 guidelines:

Elicit a three-generation family history to assess for additional family members at risk of TSC.

Offer genetic testing for family counseling or when TSC diagnosis is in question but cannot be clinically confirmed.

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Diagnostic investigations

Evaluation of cerebral involvement: as per TSCi 2013 guidelines, obtain brain MRI to assess for the presence of tubers, subependymal nodules, migrational defects, and subependymal giant cell astrocytoma in patients with suspected or newly diagnosed tuberous sclerosis.

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Medical management

Management of cerebral involvement

As per TSCi 2013 guidelines:

Perform surgical resection for acutely symptomatic subependymal giant cell astrocytoma. Consider creating CSF diversion (shunting).

Consider performing either surgical resection or initiating medical treatment with mTOR complex inhibitors for growing but otherwise asymptomatic subependymal giant cell astrocytoma. Include a discussion of the complication risks, adverse effects, cost, length of treatment, and potential impact on TSC-associated comorbidities in the decision-making process for determining the best treatment option.

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Follow-up and surveillance

Follow-up of cerebral involvement: as per TSCi 2013 guidelines, obtain MRI of the brain every 1-3 years in asymptomatic patients with TSC aged < 25 years to monitor for the new occurrence of subependymal giant cell astrocytoma. Obtain MRI more frequently in patients with large or growing subependymal giant cell astrocytoma or with subependymal giant cell astrocytoma causing ventricular enlargement but yet remaining asymptomatic, and educate their families regarding the potential of new symptoms. Continue obtaining imaging periodically in adult patients with asymptomatic subependymal giant cell astrocytoma diagnosed in childhood to ensure there is no growth.

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