Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Primer
  • Published:

Tuberous sclerosis complex

Abstract

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder that affects multiple organ systems and is caused by loss-of-function mutations in one of two genes: TSC1 or TSC2. The disorder can affect both adults and children. First described in depth by Bourneville in 1880, it is now estimated that nearly 2 million people are affected by the disease worldwide. The clinical features of TSC are distinctive and can vary widely between individuals, even within one family. Major features of the disease include tumours of the brain, skin, heart, lungs and kidneys, seizures and TSC-associated neuropsychiatric disorders, which can include autism spectrum disorder and cognitive disability. TSC1 (also known as hamartin) and TSC2 (also known as tuberin) form the TSC protein complex that acts as an inhibitor of the mechanistic target of rapamycin (mTOR) signalling pathway, which in turn plays a pivotal part in regulating cell growth, proliferation, autophagy and protein and lipid synthesis. Remarkable progress in basic and translational research, in addition to several randomized controlled trials worldwide, has led to regulatory approval of the use of mTOR inhibitors for the treatment of renal angiomyolipomas, brain subependymal giant cell astrocytomas and pulmonary lymphangioleiomyomatosis, but further research is needed to establish full indications of therapeutic treatment. In this Primer, we review the state-of-the-art knowledge in the TSC field, including the molecular and cellular basis of the disease, medical management, major knowledge gaps and ongoing research towards a cure.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Clinical manifestations of TSC are diverse and affect multiple organs.
Figure 2: Images of clinical manifestations of TSC.
Figure 3: Approximate kinetics of age-dependent clinical manifestations of TSC.
Figure 4: The two-hit tumour-suppressor gene model in TSC.
Figure 5: Canonical and non-canonical TSC signalling pathways.

Similar content being viewed by others

References

  1. Crino, P. B., Nathanson, K. L. & Henske, E. P. The tuberous sclerosis complex. N. Engl. J. Med. 355, 1345–1356 (2006).

    Article  CAS  PubMed  Google Scholar 

  2. Curatolo, P. & Bombardieri, R. Tuberous sclerosis. Handb. Clin. Neurol. 87, 129–151 (2008).

    Article  PubMed  Google Scholar 

  3. Northrup, H., Krueger, D. A. & International Tuberous Sclerosis Complex Consensus Group. Tuberous sclerosis complex diagnostic criteria update: recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference. Pediatr. Neurol. 49, 243–254 (2013). This paper provides the most current diagnostic criteria for TSC. The previous criteria were from the consensus conference in 1998.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Jones, A. C. et al. Molecular genetic and phenotypic analysis reveals differences between TSC1 and TSC2 associated familial and sporadic tuberous sclerosis. Hum. Mol. Genet. 6, 2155–2161 (1997).

    Article  CAS  PubMed  Google Scholar 

  5. Li, J., Kim, S. G. & Blenis, J. Rapamycin: one drug, many effects. Cell. Metab. 19, 373–379 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. O'Callaghan, F. J., Shiell, A. W., Osborne, J. P. & Martyn, C. N. Prevalence of tuberous sclerosis estimated by capture–recapture analysis. Lancet 351, 1490 (1998).

    Article  CAS  PubMed  Google Scholar 

  7. Hallett, L., Foster, T., Liu, Z., Blieden, M. & Valentim, J. Burden of disease and unmet needs in tuberous sclerosis complex with neurological manifestations: systematic review. Curr. Med. Res. Opin. 27, 1571–1583 (2011).

    Article  PubMed  Google Scholar 

  8. Shepherd, C. W., Gomez, M. R., Lie, J. T. & Crowson, C. S. Causes of death in patients with tuberous sclerosis. Mayo Clin. Proc. 66, 792–796 (1991).

    Article  CAS  PubMed  Google Scholar 

  9. Camfield, P. & Camfield, C. Sudden unexpected death in people with epilepsy: a pediatric perspective. Semin. Pediatr. Neurol. 12, 10–14 (2005).

    Article  PubMed  Google Scholar 

  10. Sancak, O. et al. Mutational analysis of the TSC1 and TSC2 genes in a diagnostic setting: genotype–phenotype correlations and comparison of diagnostic DNA techniques in tuberous sclerosis complex. Eur. J. Hum. Genet. 13, 731–741 (2005).

    Article  CAS  PubMed  Google Scholar 

  11. Dabora, S. L. et al. Mutational analysis in a cohort of 224 tuberous sclerosis patients indicates increased severity of TSC2, compared with TSC1, disease in multiple organs. Am. J. Hum. Genet. 68, 64–80 (2001). This paper shows that patients with TSC2 mutations had a more severe phenotype of TSC than patients with TSC1 mutations in multiple clinical measures that relate to brain, renal, dermatological and retinal involvement in TSC.

    Article  CAS  PubMed  Google Scholar 

  12. Jones, A. C. et al. Comprehensive mutation analysis of TSC1 and TSC2 and phenotypic correlations in 150 families with tuberous sclerosis. Am. J. Hum. Genet. 64, 1305–1315 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Nellist, M. et al. Targeted next generation sequencing reveals previously unidentified TSC1 and TSC2 mutations. BMC Med. Genet. 16, 10 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Tyburczy, M. E. et al. Mosaic and intronic mutations in TSC1/TSC2 explain the majority of TSC patients with no mutation identified by conventional testing. PLoS Genet. 11, e1005637 (2015). This paper highlighted the prevalence of mosaicism in TSC, indicating the importance of full-gene coverage, next-generation sequencing and TSC-related tumour analysis for mutation detection. It also indicated that it is unlikely that a third TSC gene exists.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Hoogeveen-Westerveld, M. et al. Functional assessment of TSC1 missense variants identified in individuals with tuberous sclerosis complex. Hum. Mutat. 33, 476–479 (2012).

    Article  CAS  PubMed  Google Scholar 

  16. Mayer, K., Ballhausen, W. & Rott, H. D. Mutation screening of the entire coding regions of the TSC1 and the TSC2 gene with the protein truncation test (PTT) identifies frequent splicing defects. Hum. Mutat. 14, 401–411 (1999).

    Article  CAS  PubMed  Google Scholar 

  17. Au, K. S. et al. Genotype/phenotype correlation in 325 individuals referred for a diagnosis of tuberous sclerosis complex in the United States. Genet. Med. 9, 88–100 (2007).

    Article  CAS  PubMed  Google Scholar 

  18. Lewis, J. C., Thomas, H. V., Murphy, K. C. & Sampson, J. R. Genotype and psychological phenotype in tuberous sclerosis. J. Med. Genet. 41, 203–207 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. van Eeghen, A. M., Black, M. E., Pulsifer, M. B., Kwiatkowski, D. J. & Thiele, E. A. Genotype and cognitive phenotype of patients with tuberous sclerosis complex. Eur. J. Hum. Genet. 20, 510–515 (2012).

    Article  CAS  PubMed  Google Scholar 

  20. van Eeghen, A. M., Nellist, M., van Eeghen, E. E. & Thiele, E. A. Central TSC2 missense mutations are associated with a reduced risk of infantile spasms. Epilepsy Res. 103, 83–87 (2013).

    Article  CAS  PubMed  Google Scholar 

  21. Wong, H. T. et al. Intellectual ability in tuberous sclerosis complex correlates with predicted effects of mutations on TSC1 and TSC2 proteins. J. Med. Genet. 52, 815–822 (2015).

    Article  CAS  PubMed  Google Scholar 

  22. Jansen, A. C. et al. Unusually mild tuberous sclerosis phenotype is associated with TSC2 R905Q mutation. Ann. Neurol. 60, 528–539 (2006).

    Article  CAS  PubMed  Google Scholar 

  23. Wentink, M. et al. Functional characterization of the TSC2 c.3598C>T (p. R1200W) missense mutation that co-segregates with tuberous sclerosis complex in mildly affected kindreds. Clin. Genet. 81, 453–461 (2012).

    Article  CAS  PubMed  Google Scholar 

  24. O'Connor, S. E., Kwiatkowski, D. J., Roberts, P. S., Wollmann, R. L. & Huttenlocher, P. R. A family with seizures and minor features of tuberous sclerosis and a novel TSC2 mutation. Neurology 61, 409–412 (2003).

    Article  CAS  PubMed  Google Scholar 

  25. Sampson, J. R. et al. Renal cystic disease in tuberous sclerosis: role of the polycystic kidney disease 1 gene. Am. J. Hum. Genet. 61, 843–851 (1997). Considerable renal cystic disease in TSC is shown to reflect mutational involvement of PKD1, with moscaicism for large deletions of TSC2 and PKD1 being a frequent phenomenon.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Holmes, G. L., Stafstrom, C. E. & Tuberous Sclerosis Study Goup. Tuberous sclerosis complex and epilepsy: recent developments and future challenges. Epilepsia 48, 617–630 (2007).

    Article  PubMed  Google Scholar 

  27. Kotulska, K. et al. Epilepsy in newborns with tuberous sclerosis complex. Eur. J. Paediatr. Neurol. 18, 714–721 (2014).

    Article  PubMed  Google Scholar 

  28. Jóźwiak, S. & Kotulska, K. Prevention of epileptogenesis — a new goal for epilepsy therapy. Pediatr. Neurol. 51, 758–759 (2014).

    Article  PubMed  Google Scholar 

  29. Overwater, I. E. et al. Epilepsy in children with tuberous sclerosis complex: chance of remission and response to antiepileptic drugs. Epilepsia 56, 1239–1245 (2015).

    Article  CAS  PubMed  Google Scholar 

  30. Curatolo, P., Moavero, R. & de Vries, P. J. Neurological and neuropsychiatric aspects of tuberous sclerosis complex. Lancet Neurol. 14, 733–745 (2015).

    Article  PubMed  Google Scholar 

  31. Chu-Shore, C. J., Major, P., Camposano, S., Muzykewicz, D. & Thiele, E. A. The natural history of epilepsy in tuberous sclerosis complex. Epilepsia 51, 1236–1241 (2010).

    Article  PubMed  Google Scholar 

  32. Kotulska, K. et al. Congenital subependymal giant cell astrocytomas in patients with tuberous sclerosis complex. Childs Nerv. Syst. 30, 2037–2042 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  33. Roth, J. et al. Subependymal giant cell astrocytoma: diagnosis, screening, and treatment. Recommendations from the International Tuberous Sclerosis Complex Consensus Conference 2012. Pediatr. Neurol. 49, 439–444 (2013).

    Article  PubMed  Google Scholar 

  34. Joinson, C. et al. Learning disability and epilepsy in an epidemiological sample of individuals with tuberous sclerosis complex. Psychol. Med. 33, 335–344 (2003).

    Article  CAS  PubMed  Google Scholar 

  35. Numis, A. L. et al. Identification of risk factors for autism spectrum disorders in tuberous sclerosis complex. Neurology 76, 981–987 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. de Vries, P. J. et al. Tuberous sclerosis associated neuropsychiatric disorders (TAND) and the TAND Checklist. Pediatr. Neurol. 52, 25–35 (2015). The neuropsychiatry panel coined the term TANDs to bring together all neuropsychiatric manifestations of TSC, in addition to a checklist as a guide for screening.

    Article  PubMed  Google Scholar 

  37. Taveira-DaSilva, A. M. & Moss, J. Clinical features, epidemiology, and therapy of lymphangioleiomyomatosis. Clin. Epidemiol. 7, 249–257 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  38. Meraj, R., Wikenheiser-Brokamp, K. A., Young, L. R. & McCormack, F. X. Lymphangioleiomyomatosis: new concepts in pathogenesis, diagnosis, and treatment. Semin. Respir. Crit. Care Med. 33, 486–497 (2012).

    Article  PubMed  Google Scholar 

  39. Henske, E. P. & McCormack, F. X. Lymphangioleiomyomatosis — a wolf in sheep's clothing. J. Clin. Invest. 122, 3807–3816 (2012). This is a review of the clinical features, pathophysiology and therapy of LAM, with an emphasis on future directions for research and therapy.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Cudzilo, C. J. et al. Lymphangioleiomyomatosis screening in women with tuberous sclerosis. Chest 144, 578–585 (2013).

    Article  PubMed  Google Scholar 

  41. Aubry, M. C. et al. Pulmonary lymphangioleiomyomatosis in a man. Am. J. Respir. Crit. Care Med. 162, 749–752 (2000).

    Article  CAS  PubMed  Google Scholar 

  42. Muzykewicz, D. A. et al. TSC1 and TSC2 mutations in patients with lymphangioleiomyomatosis and tuberous sclerosis complex. J. Med. Genet. 46, 465–468 (2009).

    Article  CAS  PubMed  Google Scholar 

  43. Adriaensen, M. E., Schaefer-Prokop, C. M., Duyndam, D. A., Zonnenberg, B. A. & Prokop, M. Radiological evidence of lymphangioleiomyomatosis in female and male patients with tuberous sclerosis complex. Clin. Radiol. 66, 625–628 (2011).

    Article  CAS  PubMed  Google Scholar 

  44. Bjornsson, J., Short, M. P., Kwiatkowski, D. J. & Henske, E. P. Tuberous sclerosis-associated renal cell carcinoma. Clinical, pathological, and genetic features. Am. J. Pathol. 149, 1201–1208 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. McCormack, F. X. et al. Efficacy and safety of sirolimus in lymphangioleiomyomatosis. N. Engl. J. Med. 364, 1595–1606 (2011). This is an international, multicentre, randomized, double-blind, placebo-controlled clinical trial showing that sirolimus treatment for 1 year is beneficial in patients with moderately severe LAM.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Franz, D. N. et al. Mutational and radiographic analysis of pulmonary disease consistent with lymphangioleiomyomatosis and micronodular pneumocyte hyperplasia in women with tuberous sclerosis. Am. J. Respir. Crit. Care Med. 164, 661–668 (2001).

    Article  CAS  PubMed  Google Scholar 

  47. Hayashi, T. et al. Loss of heterozygosity on tuberous sclerosis complex genes in multifocal micronodular pneumocyte hyperplasia. Mod. Pathol. 23, 1251–1260 (2010).

    Article  PubMed  Google Scholar 

  48. von Ranke, F. M. et al. Tuberous sclerosis complex: state-of-the-art review with a focus on pulmonary involvement. Lung 193, 619–627 (2015).

    Article  PubMed  Google Scholar 

  49. Jóźwiak, S., Schwartz, R. A., Janniger, C. K. & Bielicka-Cymerman, J. Usefulness of diagnostic criteria of tuberous sclerosis complex in pediatric patients. J. Child Neurol. 15, 652–659 (2000).

    Article  PubMed  Google Scholar 

  50. Ewalt, D. H., Sheffield, E., Sparagana, S. P., Delgado, M. R. & Roach, E. S. Renal lesion growth in children with tuberous sclerosis complex. J. Urol. 160, 141–145 (1998).

    Article  CAS  PubMed  Google Scholar 

  51. Bernstein, J. & Robbins, T. O. Renal involvement in tuberous sclerosis. Ann. NY Acad. Sci. 615, 36–49 (1991).

    Article  CAS  PubMed  Google Scholar 

  52. Dixon, B. P., Hulbert, J. C. & Bissler, J. J. Tuberous sclerosis complex renal disease. Nephron Exp. Nephrol. 118, e15–e20 (2011).

    Article  PubMed  Google Scholar 

  53. Bissler, J. J. & Kingswood, J. C. Renal angiomyolipomata. Kidney Int. 66, 924–934 (2004).

    Article  PubMed  Google Scholar 

  54. Rakowski, S. K. et al. Renal manifestations of tuberous sclerosis complex: incidence, prognosis, and predictive factors. Kidney Int. 70, 1777–1782 (2006).

    Article  CAS  PubMed  Google Scholar 

  55. Guo, J. et al. Tuberous sclerosis-associated renal cell carcinoma: a clinicopathologic study of 57 separate carcinomas in 18 patients. Am. J. Surg. Pathol. 38, 1457–1467 (2014).

    Article  PubMed  Google Scholar 

  56. De Waele, L., Lagae, L. & Mekahli, D. Tuberous sclerosis complex: the past and the future. Pediatr. Nephrol. 30, 1771–1780 (2015).

    Article  PubMed  Google Scholar 

  57. Teng, J. M. et al. Dermatologic and dental aspects of the 2012 International Tuberous Sclerosis Complex Consensus Statements. JAMA Dermatol. 150, 1095–1101 (2014).

    Article  PubMed  Google Scholar 

  58. O'Callaghan, F. J., Noakes, M. J., Martyn, C. N. & Osborne, J. P. An epidemiological study of renal pathology in tuberous sclerosis complex. BJU Int. 94, 853–857 (2004).

    Article  PubMed  Google Scholar 

  59. Rowley, S. A., O’Callaghan, F. J. & Osborne, J. P. Ophthalmic manifestations of tuberous sclerosis: a population based study. Br. J. Ophthalmol. 85, 420–423 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Green, A. J., Smith, M. & Yates, J. R. Loss of heterozygosity on chromosome 16p13.3 in hamartomas from tuberous sclerosis patients. Nat. Genet. 6, 193–196 (1994).

    Article  CAS  PubMed  Google Scholar 

  61. Tyburczy, M. E. et al. Sun exposure causes somatic second-hit mutations and angiofibroma development in tuberous sclerosis complex. Hum. Mol. Genet. 23, 2023–2029 (2014). This paper implicates UV-induced DNA damage as a cause of second-hit mutations and the subsequent development of TSC-associated facial angiofibromas. These data suggest that limiting UV exposure might reduce the severity of these facial lesions.

    Article  CAS  PubMed  Google Scholar 

  62. Yu, J., Astrinidis, A. & Henske, E. P. Chromosome 16 loss of heterozygosity in tuberous sclerosis and sporadic lymphangiomyomatosis. Am. J. Respir. Crit. Care Med. 164, 1537–1540 (2001).

    Article  CAS  PubMed  Google Scholar 

  63. Henske, E. P. et al. Loss of heterozygosity in the tuberous sclerosis (TSC2) region of chromosome band 16p13 occurs in sporadic as well as TSC-associated renal angiomyolipomas. Genes Chromosomes Cancer 13, 295–298 (1995).

    Article  CAS  PubMed  Google Scholar 

  64. Henske, E. P. et al. Allelic loss is frequent in tuberous sclerosis kidney lesions but rare in brain lesions. Am. J. Hum. Genet. 59, 400–406 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Au, K. S., Hebert, A. A., Roach, E. S. & Northrup, H. Complete inactivation of the TSC2 gene leads to formation of hamartomas. Am. J. Hum. Genet. 65, 1790–1795 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Karbowniczek, M., Yu, J. & Henske, E. P. Renal angiomyolipomas from patients with sporadic lymphangiomyomatosis contain both neoplastic and non-neoplastic vascular structures. Am. J. Pathol. 162, 491–500 (2003). This paper revealed that some of the vascular elements in certain AMLs have inactivation of both alleles of TSC2, resulting in a neoplastic phenotype.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Crino, P. B., Aronica, E., Baltuch, G. & Nathanson, K. L. Biallelic TSC gene inactivation in tuberous sclerosis complex. Neurology 74, 1716–1723 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  68. Han, S. et al. Phosphorylation of tuberin as a novel mechanism for somatic inactivation of the tuberous sclerosis complex proteins in brain lesions. Cancer Res. 64, 812–816 (2004).

    Article  CAS  PubMed  Google Scholar 

  69. Kwiatkowski, D. J. & Manning, B. D. Molecular basis of giant cells in tuberous sclerosis complex. N. Engl. J. Med. 371, 778–780 (2014).

    Article  CAS  PubMed  Google Scholar 

  70. Dibble, C. C. & Cantley, L. C. Regulation of mTORC1 by PI3K signaling. Trends Cell Biol. 25, 545–555 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Kim, Y. C. & Guan, K. L. mTOR: a pharmacologic target for autophagy regulation. J. Clin. Invest. 125, 25–32 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  72. Medvetz, D., Priolo, C. & Henske, E. P. Therapeutic targeting of cellular metabolism in cells with hyperactive mTORC1: a paradigm shift. Mol. Cancer Res. 13, 3–8 (2015).

    Article  CAS  PubMed  Google Scholar 

  73. Neuman, N. A. & Henske, E. P. Non-canonical functions of the tuberous sclerosis complex–Rheb signalling axis. EMBO Mol. Med. 3, 189–200 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Clements, D., Dongre, A., Krymskaya, V. P. & Johnson, S. R. Wild type mesenchymal cells contribute to the lung pathology of lymphangioleiomyomatosis. PLoS ONE 10, e0126025 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Patel, B. et al. Exosomes mediate the acquisition of the disease phenotypes by cells with normal genome in tuberous sclerosis complex. Oncogenehttp://dx.doi.org/10.1038/onc.2015.358 (2015).

  76. Prabowo, A. S. et al. Fetal brain lesions in tuberous sclerosis complex: TORC1 activation and inflammation. Brain Pathol. 23, 45–59 (2013).

    Article  CAS  PubMed  Google Scholar 

  77. Hirama, M. et al. Lymphangioleiomyomatosis diagnosed by immunocytochemical and genetic analysis of lymphangioleiomyomatosis cell clusters found in chylous pleural effusion. Intern. Med. 46, 1593–1596 (2007).

    Article  PubMed  Google Scholar 

  78. Li, C. et al. Estradiol and mTORC2 cooperate to enhance prostaglandin biosynthesis and tumorigenesis in TSC2-deficient LAM cells. J. Exp. Med. 211, 15–28 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Kaczorowska, M. et al. Cerebral tuber count and its impact on mental outcome of patients with tuberous sclerosis complex. Epilepsia 52, 22–27 (2011).

    Article  PubMed  Google Scholar 

  80. Curatolo, P. et al. Early onset epileptic encephalopathy or genetically determined encephalopathy with early onset epilepsy? Lessons learned from TSC. Eur. J. Paediatr. Neurol. 20, 203–211 (2016).

    Article  PubMed  Google Scholar 

  81. Uhlmann, E. J. et al. Astrocyte-specific TSC1 conditional knockout mice exhibit abnormal neuronal organization and seizures. Ann. Neurol. 52, 285–296 (2002).

    Article  CAS  PubMed  Google Scholar 

  82. Zeng, L. H. et al. Tsc2 gene inactivation causes a more severe epilepsy phenotype than Tsc1 inactivation in a mouse model of tuberous sclerosis complex. Hum. Mol. Genet. 20, 445–454 (2011).

    Article  CAS  PubMed  Google Scholar 

  83. Aronica, E. & Crino, P. B. Epilepsy related to developmental tumors and malformations of cortical development. Neurotherapeutics 11, 251–268 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  84. Tsai, V. et al. Fetal brain mTOR signaling activation in tuberous sclerosis complex. Cereb. Cortex 24, 315–327 (2014).

    Article  PubMed  Google Scholar 

  85. Siedlecka, M., Szlufik, S., Grajkowska, W., Roszkowski, M. & Jóźwiak, J. Erk activation as a possible mechanism of transformation of subependymal nodule into subependymal giant cell astrocytoma. Folia Neuropathol. 53, 8–14 (2015).

    Article  CAS  PubMed  Google Scholar 

  86. Longa, L. et al.TSC1 and TSC2 deletions differ in size, preference for recombinatorial sequences, and location within the gene. Hum. Genet. 108, 156–166 (2001).

    Article  CAS  PubMed  Google Scholar 

  87. Grajkowska, W. et al. Subependymal giant cell astrocytomas with atypical histological features mimicking malignant gliomas. Folia Neuropathol. 49, 39–46 (2011).

    PubMed  Google Scholar 

  88. Bolton, P. F., Park, R. J., Higgins, J. N., Griffiths, P. D. & Pickles, A. Neuro-epileptic determinants of autism spectrum disorders in tuberous sclerosis complex. Brain 125, 1247–1255 (2002).

    Article  PubMed  Google Scholar 

  89. Bolton, P. F. & Griffiths, P. D. Association of tuberous sclerosis of temporal lobes with autism and atypical autism. Lancet 349, 392–395 (1997).

    Article  CAS  PubMed  Google Scholar 

  90. Asano, E. et al. Autism in tuberous sclerosis complex is related to both cortical and subcortical dysfunction. Neurology 57, 1269–1277 (2001).

    Article  CAS  PubMed  Google Scholar 

  91. Tobino, K. et al. Differentiation between Birt–Hogg–Dubé syndrome and lymphangioleiomyomatosis: quantitative analysis of pulmonary cysts on computed tomography of the chest in 66 females. Eur. J. Radiol. 81, 1340–1346 (2012).

    Article  PubMed  Google Scholar 

  92. Carsillo, T., Astrinidis, A. & Henske, E. P. Mutations in the tuberous sclerosis complex gene TSC2 are a cause of sporadic pulmonary lymphangioleiomyomatosis. Proc. Natl Acad. Sci. USA 97, 6085–6090 (2000). This paper demonstrates that somatic, biallelic TSC2 mutations are a cause of sporadic LAM.

    Article  CAS  PubMed  Google Scholar 

  93. Strizheva, G. D. et al. The spectrum of mutations in TSC1 and TSC2 in women with tuberous sclerosis and lymphangiomyomatosis. Am. J. Respir. Crit. Care Med. 163, 253–258 (2001).

    Article  CAS  PubMed  Google Scholar 

  94. Badri, K. R. et al. Exonic mutations of TSC2/TSC1 are common but not seen in all sporadic pulmonary lymphangioleiomyomatosis. Am. J. Respir. Crit. Care Med. 187, 663–665 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Yu, J. J. et al. Estrogen promotes the survival and pulmonary metastasis of tuberin-null cells. Proc. Natl Acad. Sci. USA 106, 2635–2640 (2009).

    Article  PubMed  Google Scholar 

  96. Li, C. et al. Faslodex inhibits estradiol-induced extracellular matrix dynamics and lung metastasis in a model of lymphangioleiomyomatosis. Am. J. Respir. Cell. Mol. Biol. 49, 135–142 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Cai, X. et al. Sirolimus decreases circulating lymphangioleiomyomatosis cells in patients with lymphangioleiomyomatosis. Chest 145, 108–112 (2014).

    Article  CAS  PubMed  Google Scholar 

  98. Cai, X. et al. Phenotypic characterization of disseminated cells with TSC2 loss of heterozygosity in patients with lymphangioleiomyomatosis. Am. J. Respir. Crit. Care Med. 182, 1410–1418 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Crooks, D. M. et al. Molecular and genetic analysis of disseminated neoplastic cells in lymphangioleiomyomatosis. Proc. Natl Acad. Sci. USA 101, 17462–17467 (2004).

    Article  CAS  PubMed  Google Scholar 

  100. Karbowniczek, M. et al. Recurrent lymphangiomyomatosis after transplantation: genetic analyses reveal a metastatic mechanism. Am. J. Respir. Crit. Care Med. 167, 976–982 (2003).

    Article  PubMed  Google Scholar 

  101. Prizant, H. et al. Uterine-specific loss of Tsc2 leads to myometrial tumors in both the uterus and lungs. Mol. Endocrinol. 27, 1403–1414 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Young, L. et al. Serum VEGF-D a concentration as a biomarker of lymphangioleiomyomatosis severity and treatment response: a prospective analysis of the Multicenter International Lymphangioleiomyomatosis Efficacy of Sirolimus (MILES) trial. Lancet Respir. Med. 1, 445–452 (2013). Using data from the MILES trial, this study showed that serum VEGFD is a useful biomarker in LAM and correlates with disease severity and treatment response.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Hayashi, T. et al. Immunohistochemical study of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) in pulmonary lymphangioleiomyomatosis (LAM). Hum. Pathol. 28, 1071–1078 (1997).

    Article  CAS  PubMed  Google Scholar 

  104. Logginidou, H., Ao, X., Russo, I. & Henske, E. P. Frequent estrogen and progesterone receptor immunoreactivity in renal angiomyolipomas from women with pulmonary lymphangioleiomyomatosis. Chest 117, 25–30 (2000).

    Article  CAS  PubMed  Google Scholar 

  105. Siroky, B. J., Yin, H. & Bissler, J. J. Clinical and molecular insights into tuberous sclerosis complex renal disease. Pediatr. Nephrol. 26, 839–852 (2011).

    Article  PubMed  Google Scholar 

  106. Lin, F. et al. Expression of S-100 protein in renal cell neoplasms. Hum. Pathol. 37, 462–470 (2006).

    Article  CAS  PubMed  Google Scholar 

  107. Sarnat, H. B. & Flores-Sarnat, L. Embryology of the neural crest: its inductive role in the neurocutaneous syndromes. J. Child Neurol. 20, 637–643 (2005).

    Article  PubMed  Google Scholar 

  108. Siroky, B. J., Czyzyk-Krzeska, M. F. & Bissler, J. J. Renal involvement in tuberous sclerosis complex and Von Hippel–Lindau disease: shared disease mechanisms? Nat. Clin. Pract. Nephrol. 5, 143–156 (2009).

    CAS  PubMed  Google Scholar 

  109. Henske, E. P. Tuberous sclerosis and the kidney: from mesenchyme to epithelium, and beyond. Pediatr. Nephrol. 20, 854–857 (2005).

    Article  PubMed  Google Scholar 

  110. El-Hashemite, N., Walker, V., Zhang, H. & Kwiatkowski, D. J. Loss of Tsc1 or Tsc2 induces vascular endothelial growth factor production through mammalian target of rapamycin. Cancer Res. 63, 5173–5177 (2003).

    CAS  PubMed  Google Scholar 

  111. Knudson, A. G. Jr. Mutation and cancer: statistical study of retinoblastoma. Proc. Natl Acad. Sci. USA 68, 820–823 (1971).

    Article  PubMed  Google Scholar 

  112. El-Hashemite, N., Zhang, H., Henske, E. P. & Kwiatkowski, D. J. Mutation in TSC2 and activation of mammalian target of rapamycin signalling pathway in renal angiomyolipoma. Lancet 361, 1348–1349 (2003).

    Article  CAS  PubMed  Google Scholar 

  113. Al-Saleem, T. et al. Malignant tumors of the kidney, brain, and soft tissues in children and young adults with the tuberous sclerosis complex. Cancer 83, 2208–2216 (1998).

    Article  CAS  PubMed  Google Scholar 

  114. Wagner, A. J. et al. Clinical activity of mTOR inhibition with sirolimus in malignant perivascular epithelioid cell tumors: targeting the pathogenic activation of mTORC1 in tumors. J. Clin. Oncol. 28, 835–840 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Yang, P. et al. Renal cell carcinoma in tuberous sclerosis complex. Am. J. Surg. Pathol. 38, 895–909 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  116. Kang, S. G. et al. Two different renal cell carcinomas and multiple angiomyolipomas in a patient with tuberous sclerosis. Korean J. Urol. 51, 729–732 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  117. Pea, M. et al. Apparent renal cell carcinomas in tuberous sclerosis are heterogeneous: the identification of malignant epithelioid angiomyolipoma. Am. J. Surg. Pathol. 22, 180–187 (1998).

    Article  CAS  PubMed  Google Scholar 

  118. Sampson, J. R., Patel, A. & Mee, A. D. Multifocal renal cell carcinoma in sibs from a chromosome 9 linked (TSC1) tuberous sclerosis family. J. Med. Genet. 32, 848–850 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Tyburczy, M. E. et al. A shower of second hit events as the cause of multifocal renal cell carcinoma in tuberous sclerosis complex. Hum. Mol. Genet. 24, 1836–1842 (2015).

    Article  CAS  PubMed  Google Scholar 

  120. Consugar, M. B. et al. Characterization of large rearrangements in autosomal dominant polycystic kidney disease and the PKD1/TSC2 contiguous gene syndrome. Kidney Int. 74, 1468–1479 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Franz, D. N. et al. Efficacy and safety of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis complex (EXIST-1): a multicentre, randomised, placebo-controlled Phase 3 trial. Lancet 381, 125–132 (2013). EXIST-1 is a multicentre, randomized, double-blind, Phase III study showing the efficacy and tolerability of everolimus in patients with TSC-associated SEGAs.

    Article  CAS  Google Scholar 

  122. Bissler, J. J. et al. Everolimus for angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis (EXIST-2): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet 381, 817–824 (2013). EXIST-2 is a multicentre, randomized, double-blind, placebo-controlled trial showing the beneficial effect of everolimus treatment on AMLs in patients with TSC.

    Article  CAS  PubMed  Google Scholar 

  123. Koenig, M. K. et al. Topical rapamycin therapy to alleviate the cutaneous manifestations of tuberous sclerosis complex: a double-blind, randomized, controlled trial to evaluate the safety and efficacy of topically applied rapamycin. Drugs R. D. 12, 121–126 (2012). In a double-blind, randomized, placebo-controlled trial, topical rapamycin treatment to the face was shown to safely decrease the appearance of facial angiofibromas in patients with TSC.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Schwartz, R. A., Fernandez, G., Kotulska, K. & Jóźwiak, S. Tuberous sclerosis complex: advances in diagnosis, genetics, and management. J. Am. Acad. Dermatol. 57, 189–202 (2007).

    Article  PubMed  Google Scholar 

  125. Domanska-Pakiela, D. et al. EEG abnormalities preceding the epilepsy onset in tuberous sclerosis complex patients — a prospective study of 5 patients. Eur. J. Paediatr. Neurol. 18, 458–468 (2014).

    Article  CAS  PubMed  Google Scholar 

  126. Curatolo, P. et al. Management of epilepsy associated with tuberous sclerosis complex (TSC): clinical recommendations. Eur. J. Paediatr. Neurol. 16, 582–586 (2012).

    Article  PubMed  Google Scholar 

  127. Krueger, D. A., Northrup, H. & International Tuberous Sclerosis Complex Consensus Group. Tuberous sclerosis complex surveillance and management: recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference. Pediatr. Neurol. 49, 255–265 (2013). This paper provides an evidence-based, standardized approach for clinical surveillance and management of patients with TSC across their entire lifespan, from infancy to adulthood.

    Article  PubMed  PubMed Central  Google Scholar 

  128. Casper, K. A., Donnelly, L. F., Chen, B. & Bissler, J. J. Tuberous sclerosis complex: renal imaging findings. Radiology 225, 451–456 (2002).

    Article  PubMed  Google Scholar 

  129. Kossoff, E. H., Thiele, E. A., Pfeifer, H. H., McGrogan, J. R. & Freeman, J. M. Tuberous sclerosis complex and the ketogenic diet. Epilepsia 46, 1684–1686 (2005).

    Article  PubMed  Google Scholar 

  130. Larson, A. M., Pfeifer, H. H. & Thiele, E. A. Low glycemic index treatment for epilepsy in tuberous sclerosis complex. Epilepsy Res. 99, 180–182 (2012).

    Article  PubMed  Google Scholar 

  131. Parain, D. et al. Vagal nerve stimulation in tuberous sclerosis complex patients. Pediatr. Neurol. 25, 213–216 (2001).

    Article  CAS  PubMed  Google Scholar 

  132. Kotulska, K. et al. Long-term effect of everolimus on epilepsy and growth in children under 3 years of age treated for subependymal giant cell astrocytoma associated with tuberous sclerosis complex. Eur. J. Paediatr. Neurol. 17, 479–485 (2013).

    Article  PubMed  Google Scholar 

  133. Perek-Polnik, M., Jóźwiak, S., Jurkiewicz, E., Perek, D. & Kotulska, K. Effective everolimus treatment of inoperable, life-threatening subependymal giant cell astrocytoma and intractable epilepsy in a patient with tuberous sclerosis complex. Eur. J. Paediatr. Neurol. 16, 83–85 (2012).

    Article  PubMed  Google Scholar 

  134. Liang, S. et al. Epilepsy surgery in tuberous sclerosis complex: emphasis on surgical candidate and neuropsychology. Epilepsia 51, 2316–2321 (2010).

    Article  PubMed  Google Scholar 

  135. Rogawski, M. A. & Loscher, W. The neurobiology of antiepileptic drugs. Nat. Rev. Neurosci. 5, 553–564 (2004).

    Article  CAS  PubMed  Google Scholar 

  136. Franz, D. N. et al. Rapamycin causes regression of astrocytomas in tuberous sclerosis complex. Ann. Neurol. 59, 490–498 (2006).

    Article  CAS  PubMed  Google Scholar 

  137. Franz, D. N. et al. Everolimus for subependymal giant cell astrocytoma: 5-year final analysis. Ann. Neurol. 78, 929–938 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Jóźwiak, S., Kotulska, K., Berkowitz, N., Brechenmacher, T. & Franz, D. N. Safety of everolimus in patients younger than 3 years of age: results from EXIST-1, a randomized, controlled clinical trial. J. Pediatr. 172, 151–155.e1 (2016). This multicentre, randomized, double-blind, Phase III study shows the efficacy and tolerability of everolimus in patients with TSC who are <3 years of age with SEGA.

    Article  CAS  PubMed  Google Scholar 

  139. Tillema, J. M., Leach, J. L., Krueger, D. A. & Franz, D. N. Everolimus alters white matter diffusion in tuberous sclerosis complex. Neurology 78, 526–531 (2012).

    Article  CAS  PubMed  Google Scholar 

  140. Goldberg, H. J. et al. Everolimus for the treatment of lymphangioleiomyomatosis: a Phase II study. Eur. Respir. J. 46, 783–794 (2015).

    Article  CAS  PubMed  Google Scholar 

  141. Kingswood, C. et al. The clinical profile of tuberous sclerosis complex (TSC) in the United Kingdom: a retrospective cohort study in the Clinical Practice Research Datalink (CPRD). Eur. J. Paediatr. Neurol. 20, 296–308 (2016).

    Article  PubMed  Google Scholar 

  142. Johnson, S. R. et al. European Respiratory Society guidelines for the diagnosis and management of lymphangioleiomyomatosis. Eur. Respir. J. 35, 14–26 (2010).

    Article  CAS  PubMed  Google Scholar 

  143. Kingswood, J. C. et al. Real-world assessment of renal involvement in tuberous sclerosis complex (TSC) patients in the United Kingdom (UK). Eur. Urol. Suppl. 13, e318–e318a (2014).

    Article  Google Scholar 

  144. Kingswood, J. C. et al. TOSCA inverted question mark first international registry to address knowledge gaps in the natural history and management of tuberous sclerosis complex. Orphanet J. Rare Dis. 9, 182 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  145. Cox, J. A. et al. The natural history of renal angiomyolipomata (AMLS) in tuberous sclerosis complex (TSC). Nephrol. Dial. Transplant. 27, ii325 (2012).

    Article  Google Scholar 

  146. Bissler, J. J., Racadio, J., Donnelly, L. F. & Johnson, N. D. Reduction of postembolization syndrome after ablation of renal angiomyolipoma. Am. J. Kidney Dis. 39, 966–971 (2002).

    Article  PubMed  Google Scholar 

  147. Kessler, O. J. et al. Management of renal angiomyolipoma: analysis of 15 cases. Eur. Urol. 33, 572–575 (1998).

    Article  CAS  PubMed  Google Scholar 

  148. Kothary, N. et al. Renal angiomyolipoma: long-term results after arterial embolization. J. Vasc. Interv. Radiol. 16, 45–50 (2005).

    Article  PubMed  Google Scholar 

  149. Eijkemans, M. J. et al. Long-term follow-up assessing renal angiomyolipoma treatment patterns, morbidity, and mortality: an observational study in tuberous sclerosis complex patients in the Netherlands. Am. J. Kidney Dis. 66, 638–645 (2015).

    Article  PubMed  Google Scholar 

  150. Bissler, J. J. et al. Sirolimus for angiomyolipoma in tuberous sclerosis complex or lymphangioleiomyomatosis. N. Engl. J. Med. 358, 140–151 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Davies, D. M. et al. Sirolimus therapy for angiomyolipoma in tuberous sclerosis and sporadic lymphangioleiomyomatosis: a Phase 2 trial. Clin. Cancer Res. 17, 4071–4081 (2011).

    Article  CAS  PubMed  Google Scholar 

  152. Dabora, S. L. et al. Multicenter Phase 2 trial of sirolimus for tuberous sclerosis: kidney angiomyolipomas and other tumors regress and VEGF-D levels decrease. PLoS ONE 6, e23379 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Kingswood, J. C. et al. The effect of everolimus on renal angiomyolipoma in patients with tuberous sclerosis complex being treated for subependymal giant cell astrocytoma: subgroup results from the randomized, placebo-controlled, Phase 3 trial EXIST-1. Nephrol. Dial. Transplant. 29, 1203–1210 (2014). EXIST-1 is a multicentre, randomized, double-blind, Phase III study showing the efficacy of everolimus in reducing AML volume in patients with TSC-associated SEGA.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Franz, D. N. et al. Everolimus for subependymal giant cell astrocytoma in patients with tuberous sclerosis complex: 2-year open-label extension of the randomised EXIST-1 study. Lancet Oncol. 15, 1513–1520 (2014).

    Article  CAS  PubMed  Google Scholar 

  155. Bissler, J. J. et al. Everolimus for renal angiomyolipoma in patients with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis: extension of a randomized controlled trial. Nephrol. Dial. Transplant. 31, 111–119 (2015).

    Article  CAS  PubMed  Google Scholar 

  156. Nikolskaya, N., Cox, J. A. & Kingswood, J. C. CKD in TSC patients with different renal phenotype. Nephrol. Dial. Transplant. 29, iii350 (2014).

    Google Scholar 

  157. Serra, A. L. et al. Sirolimus and kidney growth in autosomal dominant polycystic kidney disease. N. Engl. J. Med. 363, 820–829 (2010).

    Article  CAS  PubMed  Google Scholar 

  158. Walz, G. et al. Everolimus in patients with autosomal dominant polycystic kidney disease. N. Engl. J. Med. 363, 830–840 (2010).

    Article  CAS  PubMed  Google Scholar 

  159. Canaud, G. et al. Therapeutic mTOR inhibition in autosomal dominant polycystic kidney disease: what is the appropriate serum level? Am. J. Transplant. 10, 1701–1706 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Zhou, J., Brugarolas, J. & Parada, L. F. Loss of Tsc1, but not Pten, in renal tubular cells causes polycystic kidney disease by activating mTORC1. Hum. Mol. Genet. 18, 4428–4441 (2009).

    Article  CAS  PubMed  Google Scholar 

  161. Bellack, G. S. & Shapshay, S. M. Management of facial angiofibromas in tuberous sclerosis: use of the carbon dioxide laser. Otolaryngol. Head Neck Surg. 94, 37–40 (1986).

    Article  CAS  PubMed  Google Scholar 

  162. Hofbauer, G. F. et al. The mTOR inhibitor rapamycin significantly improves facial angiofibroma lesions in a patient with tuberous sclerosis. Br. J. Dermatol. 159, 473–475 (2008).

    Article  CAS  PubMed  Google Scholar 

  163. DeKlotz, C. M., Ogram, A. E., Singh, S., Dronavalli, S. & MacGregor, J. L. Dramatic improvement of facial angiofibromas in tuberous sclerosis with topical rapamycin: optimizing a treatment protocol. Arch. Dermatol. 147, 1116–1117 (2011).

    Article  PubMed  Google Scholar 

  164. Salido, R. et al. Sustained clinical effectiveness and favorable safety profile of topical sirolimus for tuberous sclerosis — associated facial angiofibroma. J. Eur. Acad. Dermatol. Venereol. 26, 1315–1318 (2012).

    Article  CAS  PubMed  Google Scholar 

  165. Tanaka, M., Wataya-Kaneda, M., Nakamura, A., Matsumoto, S. & Katayama, I. First left-right comparative study of topical rapamycin versus vehicle for facial angiofibromas in patients with tuberous sclerosis complex. Br. J. Dermatol. 169, 1314–1318 (2013).

    Article  CAS  PubMed  Google Scholar 

  166. Nathan, N. et al. Improvement of tuberous sclerosis complex (TSC) skin tumors during long-term treatment with oral sirolimus. J. Am. Acad. Dermatol. 73, 802–808 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Leung, A. K. & Robson, W. L. Tuberous sclerosis complex: a review. J. Pediatr. Health Care 21, 108–114 (2007).

    Article  PubMed  Google Scholar 

  168. Keith, D. S., Nichols, G. A., Gullion, C. M., Brown, J. B. & Smith, D. H. Longitudinal follow-up and outcomes among a population with chronic kidney disease in a large managed care organization. Arch. Intern. Med. 164, 659–663 (2004).

    Article  PubMed  Google Scholar 

  169. Jones, A. C., Sampson, J. R., Hoogendoorn, B., Cohen, D. & Cheadle, J. P. Application and evaluation of denaturing HPLC for molecular genetic analysis in tuberous sclerosis. Hum. Genet. 106, 663–668 (2000).

    Article  CAS  PubMed  Google Scholar 

  170. Ferguson, A. P., McKinlay, I. A. & Hunt, A. Care of adolescents with severe learning disability from tuberous sclerosis. Dev. Med. Child Neurol. 44, 256–262 (2002).

    Article  PubMed  Google Scholar 

  171. Kopp, C. M., Muzykewicz, D. A., Staley, B. A., Thiele, E. A. & Pulsifer, M. B. Behavior problems in children with tuberous sclerosis complex and parental stress. Epilepsy Behav. 13, 505–510 (2008). The paper highlights the importance of the use of standardized measures to assess behavioural problems in children with TSC. It further emphasized the profound effect of these behavioural problems on parenting stress.

    Article  PubMed  Google Scholar 

  172. Pilotte, A. P., Hohos, M. B., Polson, K. M., Huftalen, T. M. & Treister, N. Managing stomatitis in patients treated with mammalian target of rapamycin inhibitors. Clin. J. Oncol. Nurs. 15, E83–E89 (2011).

    Article  PubMed  Google Scholar 

  173. Nashan, B. & Citterio, F. Wound healing complications and the use of mammalian target of rapamycin inhibitors in kidney transplantation: a critical review of the literature. Transplantation 94, 547–561 (2012).

    Article  CAS  PubMed  Google Scholar 

  174. Houde, V. P. et al. Chronic rapamycin treatment causes glucose intolerance and hyperlipidemia by upregulating hepatic gluconeogenesis and impairing lipid deposition in adipose tissue. Diabetes 59, 1338–1348 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Zuber, J. et al. Sirolimus may reduce fertility in male renal transplant recipients. Am. J. Transplant. 8, 1471–1479 (2008).

    Article  CAS  PubMed  Google Scholar 

  176. Kaplan, B., Qazi, Y. & Wellen, J. R. Strategies for the management of adverse events associated with mTOR inhibitors. Transplant. Rev. (Orlando) 28, 126–133 (2014).

    Article  Google Scholar 

  177. Jóźwiak, S. et al. Antiepileptic treatment before the onset of seizures reduces epilepsy severity and risk of mental retardation in infants with tuberous sclerosis complex. Eur. J. Paediatr. Neurol. 15, 424–431 (2011).

    Article  PubMed  Google Scholar 

  178. Walther, B., Schmitt, T. & Reitter, B. Identification of infants at risk for infantile spasms by neonatal polygraphy. Brain Dev. 9, 377–390 (1987).

    Article  CAS  PubMed  Google Scholar 

  179. Ville, D., Enjolras, O., Chiron, C. & Dulac, O. Prophylactic antiepileptic treatment in Sturge–Weber disease. Seizure 11, 145–150 (2002).

    Article  CAS  PubMed  Google Scholar 

  180. Bombardieri, R., Pinci, M., Moavero, R., Cerminara, C. & Curatolo, P. Early control of seizures improves long-term outcome in children with tuberous sclerosis complex. Eur. J. Paediatr. Neurol. 14, 146–149 (2010).

    Article  PubMed  Google Scholar 

  181. Sadowski, K., Kotulska-Jóźwiak, K. & Jóźwiak, S. Role of mTOR inhibitors in epilepsy treatment. Pharmacol. Rep. 67, 636–646 (2015).

    Article  CAS  PubMed  Google Scholar 

  182. Zeng, L. H., Xu, L., Gutmann, D. H. & Wong, M. Rapamycin prevents epilepsy in a mouse model of tuberous sclerosis complex. Ann. Neurol. 63, 444–453 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Anderl, S., Freeland, M., Kwiatkowski, D. J. & Goto, J. Therapeutic value of prenatal rapamycin treatment in a mouse brain model of tuberous sclerosis complex. Hum. Mol. Genet. 20, 4597–4604 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Meikle, L. et al. Response of a neuronal model of tuberous sclerosis to mammalian target of rapamycin (mTOR) inhibitors: effects on mTORC1 and Akt signaling lead to improved survival and function. J. Neurosci. 28, 5422–5432 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Rensing, N., Han, L. & Wong, M. Intermittent dosing of rapamycin maintains antiepileptogenic effects in a mouse model of tuberous sclerosis complex. Epilepsia 56, 1088–1097 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Way, S. W. et al. The differential effects of prenatal and/or postnatal rapamycin on neurodevelopmental defects and cognition in a neuroglial mouse model of tuberous sclerosis complex. Hum. Mol. Genet. 21, 3226–3236 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Krueger, D. A. et al. Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis. N. Engl. J. Med. 363, 1801–1811 (2010). This is a prospective, open-label, Phase I/II clinical trial in patients with TSC-associated SEGA showing a beneficial effect of everolimus treatment on reducing the volume of SEGA and the seizure frequency.

    Article  CAS  PubMed  Google Scholar 

  188. Trelinska, J. et al. Complications of mammalian target of rapamycin inhibitor anticancer treatment among patients with tuberous sclerosis complex are common and occasionally life-threatening. Anticancer Drugs 26, 437–442 (2015).

    Article  CAS  PubMed  Google Scholar 

  189. Taveira-DaSilva, A. M., Pacheco-Rodriguez, G. & Moss, J. The natural history of lymphangioleiomyomatosis: markers of severity, rate of progression and prognosis. Lymphat. Res. Biol. 8, 9–19 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Medvetz, D. et al. High-throughput drug screen identifies chelerythrine as a selective inducer of death in a TSC2-null setting. Mol. Cancer Res. 13, 50–62 (2015).

    Article  CAS  PubMed  Google Scholar 

  191. Julich, K. & Sahin, M. Mechanism-based treatment in tuberous sclerosis complex. Pediatr. Neurol. 50, 290–296 (2014).

    Article  PubMed  Google Scholar 

  192. Holt, J. F. & Dickerson, W. W. The osseous lesions of tuberous sclerosis. Radiology 58, 1–8 (1952).

    Article  CAS  PubMed  Google Scholar 

  193. Hizawa, K. et al. Gastrointestinal involvement in tuberous sclerosis. Two case reports. J. Clin. Gastroenterol. 19, 46–49 (1994).

    Article  CAS  PubMed  Google Scholar 

  194. Gould, S. R. Hamartomatous rectal polyps are common in tuberous sclerosis. Ann. NY Acad. Sci. 615, 71–80 (1991).

    Article  CAS  PubMed  Google Scholar 

  195. Jóźwiak, S., Pedich, M., Rajszys, P. & Michalowicz, R. Incidence of hepatic hamartomas in tuberous sclerosis. Arch. Dis. Child 67, 1363–1365 (1992).

    Article  PubMed  PubMed Central  Google Scholar 

  196. Sparling, J. D., Hong, C. H., Brahim, J. S., Moss, J. & Darling, T. N. Oral findings in 58 adults with tuberous sclerosis complex. J. Am. Acad. Dermatol. 56, 786–790 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  197. Flanagan, N. et al. Developmental enamel defects in tuberous sclerosis: a clinical genetic marker? J. Med. Genet. 34, 637–639 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. Larson, A. M. et al. Pancreatic neuroendocrine tumors in patients with tuberous sclerosis complex. Clin. Genet. 82, 558–563 (2012).

    Article  CAS  PubMed  Google Scholar 

  199. Wang, J. H. et al. Multi-modality imaging findings of splenic hamartoma: a report of nine cases and review of the literature. Abdom. Imaging 38, 154–162 (2013).

    Article  PubMed  Google Scholar 

  200. Jóźwiak, S., Nabbout, R., Curatolo, P. & participants of the TSC Consensus Meeting for SEGA and Epilepsy Management. Management of subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis complex (TSC): clinical recommendations. Eur. J. Paediatr. Neurol. 17, 348–352 (2013).

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

The work of S.J. in this study has been partially supported by the 7th Framework Programme of European Commission within the large-scale integrating project EPISTOP (Proposal No. 602391–2). The work of E.P.H. was partially supported by the Lucy J. Engles Program in TSC/LAM Research. E.A.T. acknowledges the Carol and James Herscot Center for Children and Adults with TSC at Massachusetts General Hospital. The authors are grateful to J. Nijmeh for assistance with preparation of the manuscript.

Author information

Authors and Affiliations

Authors

Contributions

Introduction (E.P.H.); Epidemiology (E.A.T., E.P.H., J.C.K., J.R.S. and S.J.); Mechanisms/pathophysiology (E.A.T., E.P.H., J.C.K., J.R.S. and S.J.); Diagnosis, screening and prevention (E.A.T., J.R.S. and S.J.); Management (E.A.T., E.P.H., J.C.K., J.R.S. and S.J.); Quality of life (E.A.T. and J.C.K.); Outlook (E.A.T., E.P.H., J.C.K., J.R.S. and S.J.); Overview of Primer (E.P.H.). E.A.T. and E.P.H. contributed equally to this work.

Corresponding author

Correspondence to Elizabeth P. Henske.

Ethics declarations

Competing interests

S.J. has been a consultant for UCB Pharma and Eisai, has received speakers honoraria from Novartis and is a site principal investigator for Novartis clinical trials. J.R.S. has received grant funding and honoraria from Novartis. J.C.K. has received honoraria for lectures and consultancy from Novartis. E.A.T. is a consultant for GW Pharmaceuticals and Zogenix, has received grants from GW Pharmaceuticals, Lundbeck and Cyberonics, is a site principal investigator for GW Pharmaceuticals and Zogenix clinical trials and has been a site principal investigator for Novartis clinical trials. E.P.H. has been a consultant to LAM Therapeutics and was an investigator on a Novartis-sponsored trial of everolimus in lymphangioleiomyomatosis, for which no compensation or salary support was provided.

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Henske, E., Jóźwiak, S., Kingswood, J. et al. Tuberous sclerosis complex. Nat Rev Dis Primers 2, 16035 (2016). https://doi.org/10.1038/nrdp.2016.35

Download citation

  • Published:

  • DOI: https://doi.org/10.1038/nrdp.2016.35

This article is cited by

Search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer