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Dermatologic Manifestations of Tuberous Sclerosis

  • Author: Rabindranath Nambi, MD; Chief Editor: Dirk M Elston, MD  more...
 
Updated: Apr 15, 2016
 

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; most current reports refer to the condition as tuberous sclerosis complex.

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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.[1]

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).[2, 3, 4, 5] 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.[6] Hamartin and tuberin heterodimerize and inhibit mTOR, the mammalian target of rapamycin.[7]

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.[8, 9] 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 very small proportion of families exist whose genetic localization has not been determined.

Mammalian target of rapamycin

Mammalian target of rapamycin (mTOR) is a key player in pathways involved for cellular growth, proliferation, and survival via a cytoplasmic serine/threonine kinase .In cells that lack either TSC1 or TSC2, mTOR activity is increased many-fold, and this would cause uninhibited growth and subsequent hamartomas in various organs. mTOR inhibitors, which have already been used in some cancers, could play a role in tumor lysis or shrinkage owing to the above pathways being altered.

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Epidemiology

Frequency

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

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.[10]

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Prognosis

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.

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Contributor Information and Disclosures
Author

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

Disclosure: Nothing to disclose.

Specialty Editor Board

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, Texas Medical Association, Association of Military Dermatologists, Texas Dermatological Society

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

Disclosure: Nothing to disclose.

Chief Editor

Dirk M Elston, MD Professor and Chairman, Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina College of Medicine

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

Disclosure: Nothing to disclose.

Additional Contributors

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, Southern Medical Association

Disclosure: Nothing to disclose.

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

  2. Povey S, Burley MW, Attwood J, et al. Two loci for tuberous sclerosis: one on 9q34 and one on 16p13. Ann Hum Genet. 1994 May. 58:107-27. [Medline].

  3. Franz DN. Diagnosis and management of tuberous sclerosis complex. Semin Pediatr Neurol. 1998 Dec. 5(4):253-68. [Medline].

  4. Kwiatkowski DJ, Short MP. Tuberous sclerosis. Arch Dermatol. 1994 Mar. 130(3):348-54. [Medline].

  5. Roach ES, Delgado MR. Tuberous sclerosis. Dermatol Clin. 1995 Jan. 13(1):151-61. [Medline].

  6. 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. 2006 Jan 15. 15(2):287-97. [Medline].

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

  8. Karbowniczek M, Henske EP. The role of tuberin in cellular differentiation: are B-Raf and MAPK involved?. Ann N Y Acad Sci. 2005 Nov. 1059:168-73. [Medline].

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

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

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

  12. Roach ES, Gomez MR, Northrup H. Tuberous sclerosis complex consensus conference: revised clinical diagnostic criteria. J Child Neurol. 1998 Dec. 13(12):624-8. [Medline].

  13. Northrup H, Krueger DA, International Tuberous Sclerosis Complex Consensus Group. Tuberous sclerosis complex diagnostic criteria update: recommendations of the 2012 Iinternational Tuberous Sclerosis Complex Consensus Conference. Pediatr Neurol. 2013 Oct. 49 (4):243-54. [Medline].

  14. Greenwald MJ, Paller AS. Ocular and dermatologic manifestation of neurocutaneous syndromes. Dermatol Clin. 1992 Jul. 10(3):623-39. [Medline].

  15. Cross JH. Neurocutaneous syndromes and epilepsy-issues in diagnosis and management. Epilepsia. 2005. 46 Suppl 10:17-23. [Medline].

  16. Quigg M, Miller JQ. Clinical findings of the phakomatoses: tuberous sclerosis. Neurology. 2005 Nov 22. 65(10):E22-3. [Medline].

  17. Williams JM, Racadio JM, Johnson ND, Donnelly LF, Bissler JJ. Embolization of renal angiomyolipomata in patients with tuberous sclerosis complex. Am J Kidney Dis. 2006 Jan. 47(1):95-102. [Medline].

  18. Altman NR, Purser RK, Post MJ. Tuberous sclerosis: characteristics at CT and MR imaging. Radiology. 1988 May. 167(2):527-32. [Medline].

  19. Viswanath V, Thakur P, Pund P. Use of Topical Rapamycin in Facial Angiofibromas in Indian Skin Type. Indian J Dermatol. 2016 Jan-Feb. 61 (1):119. [Medline].

  20. Tuberous Sclerosis Association. Clinical guidelines for the care of patients with Tuberous Sclerosis Complex. England: Birmingham; September 2011. [Full Text].

 
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Facial angiofibromas in a young man with tuberous sclerosis complex.
Dysplastic periungual fibroma involving the great toe in a patient with tuberous sclerosis.
Table. Clinical Criteria for Diagnosing Tuberous Sclerosis Complex
Major Features Minor Features
Hypomelanotic macules (≥3, at least 5 mm in diameter) Confetti skin lesions
Angiofibromas (≥3) or fibrous cephalic plaque Dental enamel pits (>3)
Ungual fibromas (≥2) Intraoral fibromas (≥2)
Shagreen patch Retinal achromatic patch
Multiple retinal hamartomas Multiple renal cysts
Cortical dysplasiasa Nonrenal hamartomas
Subependymal nodules  
Subependymal giant cell astrocytoma  
Cardiac rhabdomyoma  
Lymphangioleiomyomatosis (LAM) plus  
Angiomyolipomas (≥2)b  
a Includes tubers and cerebral white matter radial migration lines.



b A combination of the two major clinical features (LAM and angiomyolipomas) without other features does not meet criteria for a definite diagnosis.



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