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Tuberous sclerosis complex

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Description

Tuberous sclerosis complex is a genetic disorder characterized by the growth of numerous noncancerous (benign) tumors in many parts of the body. These tumors can occur in the skin, brain, kidneys, and other organs, in some cases leading to significant health problems. Tuberous sclerosis complex also causes developmental problems, and the signs and symptoms of the condition vary from person to person.

Virtually all affected people have skin abnormalities, including patches of unusually light-colored skin, areas of raised and thickened skin, and growths under the nails. Tumors on the face called facial angiofibromas are also common beginning in childhood.

Tuberous sclerosis complex often affects the brain, resulting in a pattern of behaviors called TSC-associated neuropsychiatric disorders (TAND). These disorders include hyperactivity, aggression, psychiatric conditions, intellectual disability, and problems with communication and social interaction (autism spectrum disorder). Some individuals with tuberous sclerosis complex have seizures or benign brain tumors that can cause serious or life-threatening complications.

Kidney tumors are common in people with tuberous sclerosis complex; these growths can cause severe problems with kidney function and may be life-threatening in some cases. Additionally, tumors can develop in the heart and the light-sensitive tissue at the back of the eye (the retina). Some women with tuberous sclerosis complex develop lymphangioleiomyomatosis (LAM), which is a lung disease characterized by the abnormal overgrowth of smooth muscle-like tissue in the lungs that cause coughing, shortness of breath, chest pain, and lung collapse.

Frequency

Tuberous sclerosis complex affects about 1 in 6,000 people.

Causes

Mutations in the TSC1 or TSC2 gene can cause tuberous sclerosis complex. The TSC1 and TSC2 genes provide instructions for making the proteins hamartin and tuberin, respectively. Within cells, these two proteins likely work together to help regulate cell growth and size. The proteins act as tumor suppressors, which normally prevent cells from growing and dividing too fast or in an uncontrolled way.

People with tuberous sclerosis complex are born with one mutated copy of the TSC1 or TSC2 gene in each cell. This mutation prevents the cell from making functional hamartin or tuberin from the altered copy of the gene. However, enough protein is usually produced from the other, normal copy of the gene to regulate cell growth effectively. For some types of tumors to develop, a second mutation involving the other copy of the TSC1 or TSC2 gene must occur in certain cells during a person's lifetime.

When both copies of the TSC1 gene are mutated in a particular cell, that cell cannot produce any functional hamartin; cells with two altered copies of the TSC2 gene are unable to produce any functional tuberin. The loss of these proteins allows the cell to grow and divide in an uncontrolled way to form a tumor. In people with tuberous sclerosis complex, a second TSC1 or TSC2 mutation typically occurs in multiple cells over an affected person's lifetime. The loss of hamartin or tuberin in different types of cells leads to the growth of tumors in many different organs and tissues.

Inheritance

Tuberous sclerosis complex has an autosomal dominant pattern of inheritance, which means one copy of the altered gene in each cell is sufficient to increase the risk of developing tumors and other problems with development. In about one-third of cases, an affected person inherits an altered TSC1 or TSC2 gene from a parent who has the disorder. The remaining two-thirds of people with tuberous sclerosis complex are born with new mutations in the TSC1 or TSC2 gene. These cases, which are described as sporadic, occur in people with no history of tuberous sclerosis complex in their family. TSC1 mutations appear to be more common in familial cases of tuberous sclerosis complex, while mutations in the TSC2 gene occur more frequently in sporadic cases.

Rarely, individuals with tuberous sclerosis complex do not have an identified mutation in the TSC1 or TSC2 gene. Research suggests that in these cases the condition may be caused by a random mutation in the TSC1 or TSC2 gene that occurs very early in development. As a result, some of the body's cells have a normal version of the gene, while others have the mutated version. This situation is called mosaicism.

Other Names for This Condition

  • Bourneville disease
  • Bourneville phakomatosis
  • cerebral sclerosis
  • epiloia
  • sclerosis tuberosa
  • tuberose sclerosis

Additional Information & Resources

Genetic and Rare Diseases Information Center

Research Studies from ClinicalTrials.gov

Catalog of Genes and Diseases from OMIM

Scientific Articles on PubMed

References

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  • Curatolo P, Bombardieri R, Jozwiak S. Tuberous sclerosis. Lancet. 2008 Aug 23;372(9639):657-68. doi: 10.1016/S0140-6736(08)61279-9. Review. Citation on PubMed
  • Franz DN, Bissler JJ, McCormack FX. Tuberous sclerosis complex: neurological, renal and pulmonary manifestations. Neuropediatrics. 2010 Oct;41(5):199-208. doi: 10.1055/s-0030-1269906. Epub 2011 Jan 5. Review. Citation on PubMed or Free article on PubMed Central
  • Hyman MH, Whittemore VH. National Institutes of Health consensus conference: tuberous sclerosis complex. Arch Neurol. 2000 May;57(5):662-5. Review. Citation on PubMed
  • Lewis JC, Thomas HV, Murphy KC, Sampson JR. Genotype and psychological phenotype in tuberous sclerosis. J Med Genet. 2004 Mar;41(3):203-7. Citation on PubMed or Free article on PubMed Central
  • Maria BL, Deidrick KM, Roach ES, Gutmann DH. Tuberous sclerosis complex: pathogenesis, diagnosis, strategies, therapies, and future research directions. J Child Neurol. 2004 Sep;19(9):632-42. Citation on PubMed
  • Northrup H, Koenig MK, Pearson DA, Au KS. Tuberous Sclerosis Complex. 1999 Jul 13 [updated 2020 Apr 16]. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020. Available from http://www.ncbi.nlm.nih.gov/books/NBK1220/ Citation on PubMed
  • Orlova KA, Crino PB. The tuberous sclerosis complex. Ann N Y Acad Sci. 2010 Jan;1184:87-105. doi: 10.1111/j.1749-6632.2009.05117.x. Review. Citation on PubMed or Free article on PubMed Central
  • Rosser T, Panigrahy A, McClintock W. The diverse clinical manifestations of tuberous sclerosis complex: a review. Semin Pediatr Neurol. 2006 Mar;13(1):27-36. Review. Citation on PubMed
  • Schwartz RA, Fernández G, Kotulska K, Jóźwiak S. Tuberous sclerosis complex: advances in diagnosis, genetics, and management. J Am Acad Dermatol. 2007 Aug;57(2):189-202. Review. Citation on PubMed
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