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Tuberous Sclerosis

HomePatientsLung Disease Week at the ATS2018Tuberous Sclerosis ▶ General Information
General Information

tsc

Who is at risk?

Tuberous sclerosis complex (TSC) is a genetic disorder that can affect both children and adults. Recent incident rates have been estimated between 1/5,000 to 1/10,000 live births and the prevalence is estimated around 1 in 20,000.  While TSC is an autosomal dominant disorder, approximately two-thirds of patients have sporadic mutations.  

Genetics

The TSC1 (hamartin) gene on chromosome 9 and the TSC2 (tuberin) gene on chromosome 16 have been implicated in TSC.  In familial TSC cases, mutations in TSC1 and TSC2 genes are found nearly equally. However, in sporadic cases, TSC2 gene mutations are found with much more frequency. TSC2 mutations have been implicated in nearly 80% of sporadic cases. Mutations are found in 75-90% of patients who undergo molecular testing of the TSC1 and TSC2 genes; larger deletions are seen more commonly in the TSC2 genes. It should be noted that normal testing does not exclude TSC.

Symptoms

TSC is a multisystem disorder and many organ systems can be involved.   The most commonly involved organ systems include the skin and nervous system with reports of up to 90% of patients with TSC having involvement in these organ systems.  Patients with TSC have an increased risk of invasive malignancies typically found in the kidneys, brain and soft tissues. While a classic symptomatic triad includes seizures, mental retardation and facial adenoma sabaceum, other common manifestations by organ systems are listed below:

  • Neurologic: Subependymal giant cell tumors, glioneuronal hamartomas, white matter heterotopia, epilepsy, cognitive impairment, behavioral problems and autism
  • Dermatologic: Hypomelanotic macules, Shagreen patches (thick, elevated rough skin), Ash-leaf spots, angiofibromas and distinctive brown fibrous patches on the forehead
  • Pulmonary: cystic lung disease – identical to lymphangioleiomyomatosis (LAM)
  • Cardiovascular: rhabdomyoma
  • Renal: Angiomyolipomas
  • Ophthalmic: Retinal hamartomas, angiofibromas of the eyelids and refractive errors

Patients with lung involvement usually do not present with the classic symptomatic triad. The proportion of females with lung manifestation of TSC has been estimated at 30-50%, while estimates of lung involvement in men is around 10%. Manifestations of lung involvement include dyspnea, spontaneous pneumothorax and hemoptysis. The recent TSC Consensus Conference report now recommends all female patients with TSC who are age 18 and over should undergo computerized tomography (CT) scan and pulmonary function testing.

Diagnosis

The diagnostic criteria for TSC were updated by the International Tuberous Sclerosis Complex Consensus group in 2012. The diagnosis of TSC can be made both on genetic or clinical grounds. This indicates that a pathogenic gene mutation found on TSC1 or TSC2 is sufficient to make a diagnosis regardless of the clinical features. The clinical features are classified into major and minor features. Based on these features, there are two possible designations: "definite" and "possible" diagnosis. A "definite" diagnosis requires at least two major features or one major feature plus two or more minor features. A "probable" diagnosis requires one major or two or more minor features.

Prognosis and Management

TSC is a variable disease. Depending on the involvement, patients can have a normal life expectancy. TSC is typically a progressive disorder with features that are more prevalent at different stages of life. For example, during childhood, the dermatologic features typically become more noticeable. In adulthood, features such as angiolipomas and LAM are more prevalent. 

Previously, management of TSC had centered around symptomatic control such as managing seizures in early childhood to prevent developmental delay and avoiding cigarette smoking. However, advances in the understanding of the role of cell signaling mediated by the mechanistic target of rapamycin (mTOR) has lead to medical therapies. Everolimus is now being used in patients with TSC.  The US Food and Drug Administration has approved another mTOR inhibitor, sirolimus, for use in patients with moderate-to-severe TSC associated LAM.  Lung transplantation may also be in option in some patients with advanced lung disease.

 

Sources:
1. Northrup H, Krueger DA.  Tuberous Sclerosis Complex Diagnostic Criteria Update: Recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference.  Pediatric Neurology 2013;49:243-254
2. Krueger DA, Northrup H.  Tuberous Sclerosis Complex Surveillance and Management: Recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference.  Pediatric Neurology 2013;49:255-265
2. Crino PB, Nathanson KL, Henske EP. The Tuberous Sclerosis Complex. New England Journal of Medicine 2006;355:1345-56.
3. Hinton RB, Prakash A, Romp RL et al.  Cardiovascular Manifestations of Tuberous Sclerosis Complex and Summary of the Revised Diagnostic Criteria and Surveillance and Management Recommendations from the International Tuberous Sclerosis Consensus Group.   Journal of the American Heart Association 2014;3:e001493.


Four Facts About Tuberous Sclerosis

  1. TSC is a genetic disorder affecting 50,000 in the USA and 1 million worldwide.
  1. TSC causes tumors to form in the vital organs, primarily in the brain, eyes, heart, kidneys, skin, and lungs.
  1. Lymphangioleiomyomatosis (LAM) occurs in up to 49% of women with TSC (Muzykewicz et al, 2009; Adriansen et al, 2011; Cudzilo et al, 2013).
  1. TSC affects no two people alike, not even identical twins.