Dermatologic Manifestations of Tuberous Sclerosis
- Author: Rabindranath Nambi, MD; Chief Editor: Dirk M Elston, MD more...
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.
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).[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. Hamartin and tuberin heterodimerize and inhibit mTOR, the mammalian target of rapamycin.
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.
The frequency of tuberous sclerosis worldwide is 1 case in 5,800-30,000 persons.
No racial predilection has been noted for tuberous sclerosis.
No sex predilection has been noted for tuberous sclerosis.
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.
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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|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 giant cell astrocytoma|
|Lymphangioleiomyomatosis (LAM) plus|
|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.