Dermatologic Manifestations of Tuberous Sclerosis

Updated: Sep 24, 2021
  • Author: Rabindranath Nambi, MD; Chief Editor: Dirk M Elston, MD  more...
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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. In 1880, Désiré-Magloire 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. [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 and tuberin heterodimerize and inhibit mammalian target of rapamycin (mTOR), the mammalian target of rapamycin. [6]

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. [7, 8] 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.

MicroRNA-34a has been shown to be highly overexpressed in cortical tubers during fetal and early postnatal brain development. miR-34a negatively regulates mTORC1 and may also contribute to abnormal corticogenesis in tuberous sclerosis complex (TSC). [9]

Experiments in human cell lines, mice, Drosophila, and Caenorhabditis elegans have shown that endonuclease G (ENDOG) plays a protective role against the development of TSC. ENDOG causes autophagy by suppressing mTOR signalling and activating the DNA damage response, offering an alternative pathogenesis. [10]

Building on the newer pathways for pathogenesis includes the E3 ubiquitin ligase Peli1 as an important regulator of T-cell metabolism and antitumor immunity. Peli1 regulates the activation of a metabolic kinase, mTORC1, through its interaction with mTORC1 inhibitory proteins TSC1 and TSC2. Peli1 causes nondegradative ubiquitination of TSC1 and promotes TSC1-TSC2 dimerization and TSC2 stabilization. Hence, Peli1 is regarded as a novel regulator of mTORC1 and downstream mTORC1-mediated actions on T-cell metabolism and antitumor activity. [11]

The mechanisms of cellular energy sensing and AMPK-mediated mTORC1 inhibition are not fully delineated. A newer candidate in the pathogenesis of TSC is RIPK1, which promotes mTORC1 inhibition during energetic stress. RIPK1 mediates between AMPK and TSC2 and causes TSC2 phosphorylation at Ser1387. Loss of RIPK1 results in high basal mTORC1 activity, leading to accumulation of RIPK3 and CASP8 and sensitization to cell death. RIPK1-deficient cells are unable to cope with energetic stress and are vulnerable to low glucose levels and metformin. These findings elaborate on the regulation of mTORC1 during energetic stress and interactions between prosurvival and prodeath pathways. [12]

Mouse models and clinical studies of TSC have supported the glial dysfunction theory in the pathophysiology of epilepsy and TSC-associated neuropsychiatric disorders (TAND).The role of astrocytes, microglia, and oligodendrocytes in the pathophysiology of epilepsy and TANDs in TSC has been analyzed. Targeting glia cells may be considered in developing novel treatments for the neurological manifestations of TSC. [13]

Studies have provided new evidence on the role of exosomes and noncoding RNA cargo (including miR-142-3p, miR-223-3p, and miR-21-5p ) in the neuroinflammatory cascade of epilepsy and may help in the development of novel biomarkers and therapeutic approaches for the treatment of drug-resistant epilepsy. [14]

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. [15]



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.