Dermatologic Manifestations of Tuberous Sclerosis 

  • Author: Rabindranath Nambi, MD, DD, DipNB; Chief Editor: Dirk M Elston, MD   more...
 
Updated: Jan 11, 2010
 

Background

Tuberous sclerosis is a genetic disorder affecting cellular differentiation and proliferation, which results in hamartoma formation in many organs (eg, skin, brain, eye, kidney, heart).

Von Recklinghausen first described tuberous sclerosis in 1862. Bourneville coined the term sclerose tubereuse, from which the name of the disease has evolved. Sherlock coined the term epiloia, encompassing the clinical triad of epilepsy, low intelligence, and adenoma sebaceum. The term tuberous sclerosis complex (TSC) is now widely used, emphasizing the variegated nature of its manifestations.

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Pathophysiology

The inheritance is autosomal dominant, while up to 50-70% of cases of tuberous sclerosis have been attributed to new mutations. This high percentage of mutations may be reduced after careful examination and detailed investigation of apparently healthy parents, who on closer inspection may have disease features.

Two genetic loci for tuberous sclerosis have been identified so far. The first gene maps to chromosome 9, specifically 9q34 (TSC1); the second gene maps to chromosome 16, specifically 16p13 (TSC2).[1] Tuberin, the protein gene product of TSC2, was the first of the affected proteins to be isolated. Tuberin shows a small region of homologic identity to the catalytic domain of the Rap 1 guanosine triphosphatase (GTPase) activity protein (Rap 1 GAP). Rap 1 is a member of a group of proteins involved in the regulation of cell proliferation and differentiation. Loss of tuberin activity is thought to lead to activation of Rap 1 in tumors. Hamartin, the TSC1 second gene product, has been isolated and may function as a tumor suppressor.[2] Hamartin and tuberin heterodimerize and inhibit mTOR, the mammalian target of rapamycin.[3]

Interestingly, hamartin and tuberin have been shown to have coiled coil domains that interact with each other. Hamartin and tuberin are thought to act synergistically to regulate cellular growth and differentiation.[4, 5] The deregulation in organogenesis results in tumors, which may affect any organ in the body. Most of the tumors represent hamartomas and, in many organs, resemble embryonic cells, suggesting that the defect occurs at an early stage in life. A small proportion of families exist whose genetic localization has not been determined.

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Epidemiology

Frequency

United States

The frequency of tuberous sclerosis in the United States is 1 case in 5,800-30,000 persons.

International

International frequency for tuberous sclerosis is the same as US frequency.

Mortality/Morbidity

Tuberous sclerosis shows a wide variety of clinical expressions. Some individuals are severely affected, while others have very few features. Forme frustes are common. An accurate estimation of the course in an individual with tuberous sclerosis depends on the extent of involvement. About a quarter of severely affected infants are thought to die before age 10 years, and 75% die before age 25 years; however, the prognosis for the individual diagnosed late in life with few cutaneous signs depends on the associated internal tumors.

Race

No racial predilection has been noted for tuberous sclerosis.

Sex

No sex predilection has been noted for tuberous sclerosis.

Age

Most tuberous sclerosis patients are diagnosed between ages 2 and 6 years. Cardiac and cortical tubers develop at infancy, while skin lesions are seen in more than 90% of patients at all ages. The ash-leaf macule can be present at birth, while the facial angiofibroma and ungual fibromas can develop in late adolescence. Wand et al report a case of tuberous sclerosis first diagnosed in a military pilot at age 22 years.[6]

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Contributor Information and Disclosures
Author

Rabindranath Nambi, MD, DD, DipNB  Consulting Staff, Department of Dermatology, Dudley Group of Hospitals, UK

Disclosure: Nothing to disclose.

Specialty Editor Board

Eleanor E Sahn, MD  Director, Division of Pediatric Dermatology, Associate Professor, Departments of Dermatology and Pediatrics, Medical University of South Carolina

Eleanor E Sahn, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, and Southern Medical Association

Disclosure: Nothing to disclose.

Richard P Vinson, MD  Assistant Clinical Professor, Department of Dermatology, Texas Tech University Health Sciences Center, Paul L Foster School of Medicine; Consulting Staff, Mountain View Dermatology, PA

Richard P Vinson, MD is a member of the following medical societies: American Academy of Dermatology, Association of Military Dermatologists, Texas Dermatological Society, and Texas Medical Association

Disclosure: Nothing to disclose.

Van Perry, MD  Assistant Professor, Department of Medicine, Division of Dermatology, University of Texas School of Medicine at San Antonio

Van Perry, MD is a member of the following medical societies: American Academy of Dermatology and American Society for Laser Medicine and Surgery

Disclosure: Nothing to disclose.

Glen H Crawford, MD  Assistant Clinical Professor, Department of Dermatology, University of Pennsylvania School of Medicine; Chief, Division of Dermatology, The Pennsylvania Hospital

Glen H Crawford, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, Phi Beta Kappa, and Society of USAF Flight Surgeons

Disclosure: Nothing to disclose.

Chief Editor

Dirk M Elston, MD  Director, Department of Dermatology, Geisinger Medical Center

Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Nothing to disclose.

References

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  2. Astrinidis A, Senapedis W, Henske EP. Hamartin, the tuberous sclerosis complex 1 gene product, interacts with polo-like kinase 1 in a phosphorylation-dependent manner. Hum Mol Genet. Jan 15 2006;15(2):287-97. [Medline].

  3. Ellisen LW. Growth control under stress: mTOR regulation through the REDD1-TSC pathway. Cell Cycle. Nov 2005;4(11):1500-02. [Medline].

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  5. van Slegtenhorst M, Nellist M, Nagelkerken B, et al. Interaction between hamartin and tuberin, the TSC1 and TSC2 gene products. Hum Mol Genet. Jun 1998;7(6):1053-7. [Medline].

  6. Wand O, Blum S, Shachar E, et al. Tuberous sclerosis in a military pilot. Aviat Space Environ Med. Jul 2009;80(7):657-9. [Medline].

  7. Roach ES, DiMario FJ, Kandt RS, Northrup H. Tuberous Sclerosis Consensus Conference: recommendations for diagnostic evaluation. National Tuberous Sclerosis Association. J Child Neurol. Jun 1999;14(6):401-7. [Medline].

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  18. Tuberous Sclerosis Association. Clinical guidelines for the care of patients with Tuberous Sclerosis Complex. Available at: http://www.tuberous-sclerosis.org. England: Birmingham; April, 2002.

  19. Flinter FA, Neville BG. Examining the parents of children with tuberous sclerosis. Lancet. Nov 15 1986;2(8516):1167. [Medline].

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