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Genetics of Tuberous Sclerosis

  • Author: Robert A Schwartz, MD, MPH; Chief Editor: Luis O Rohena, MD  more...
Updated: Mar 27, 2015


Tuberous sclerosis complex (TSC) is the second most common neurocutaneous disease.[1] Tuberous sclerosis complex is inherited in an autosomal dominant pattern, although the rate of spontaneous mutation is high. Formerly characterized by the clinical triad of mental retardation, epilepsy, and facial angiofibromas, patients with tuberous sclerosis complex may present with a broad range of clinical symptoms because of variable expressivity. Tuberous sclerosis complex may affect many organs, most commonly the brain, skin, eyes, heart, kidneys, and lungs. Common features include cortical tubers, subependymal nodules (SENs), subependymal giant cell astrocytomas (SEGAs), facial angiofibromas, hypomelanotic spots known as Fitzpatrick patches (ash-leaf spots), cardiac rhabdomyomas, and renal angiomyolipomas.

Mutations in either of 2 genes (TSC1 and TSC2) have been determined to cause tuberous sclerosis complex; however, diagnosis continues to be based on clinical manifestations.[2] . Molecular analysis is helpful in confirming a diagnosis and genetic counseling.

This article elucidates the various neoplasms, along with their clinical significance, and suggest suitable evaluation and management strategies.



Molecular genetics and pathogenesis

Tuberous sclerosis complex has a broad clinical spectrum and affects almost every organ system.[3] Tuberous sclerosis complex is an inherited disorder characterized by hamartomas in different body organs, mainly in the brain, skin, kidney, liver, lung, and heart.

The hamartomas in the brain called cortical tubers are composed of abnormal glial and neural cells, and the size, number, and location vary among patients. Differences in diffusion properties of white matter between tuberous sclerosis complex and control subjects suggest disorganized and structurally compromised axons with poor myelination. The visual and social cognition systems appear to be differentially involved.[4]

The number of tubers may correlate with the severity of seizures. Other CNS manifestations include SENs and SEGAs. SENs are typically located on the surface of the lateral ventricles, giving a candle-dripping appearance, and they tend to calcify during childhood. SENs occasionally give rise to SEGAs, which develop in the Monro foramen and may cause signs and symptoms of hydrocephalus and increased intracranial pressure as they enlarge.

Skin lesions include ash-leaf spots, confetti lesions, facial angiofibromas, shagreen patches, fibrous plaques, and periungual fibromas. The hypopigmentation of ash-leaf spots is due to smaller melanosomes and defective transfer of melanin to keratinocytes. Fibromas, plaques, and patches are due to fibrosis with abnormal collagen and blood vessel accumulation.

Renal manifestations of tuberous sclerosis complex include angiomyolipomas and renal cysts. Angiomyolipomas, found in 70-80% of patients with tuberous sclerosis complex, are composed of blood vessels, smooth muscle, adipose tissue, and connective tissue. The gene for polycystic kidney disease (PKD), PKD1, is contiguous with the TSC2 gene on chromosome 16, and patients with tuberous sclerosis complex occasionally have symptoms of PKD.

Cardiac involvement is in the form of hamartomas, namely rhabdomyomas.

Pulmonary lesions are lymphangioleiomyomatosis (LAM) and pulmonary cysts. These lesions are composed of blood vessels, adipose tissue, and smooth muscle in abnormal arrangements.

Ocular involvement includes retinal hamartomas or astrocytomas that may calcify but rarely lead to decreased visual acuity or other symptoms.

Phalangeal cysts may develop in the hands and feet, and sclerotic lesions may develop in the pelvis or the spine.

The genes responsible for tuberous sclerosis complex have been identified. In 1993, TSC2, located on chromosome 16, was the first gene discovered to be involved in tuberous sclerosis complex. TSC1 is located on chromosome 9 and was identified in 1997. TSC1 encodes for the protein hamartin; TSC2, encodes for the protein tuberin. Mutations in either TSC1 or TSC2, which are tumor suppressor genes that work together to facilitate tumor suppression, cause tuberous sclerosis complex.[5]

The function and interaction of hamartin and tuberin are not yet fully understood, although they may function as tumor suppressors. Knudson's 2-hit model of tumorigenesis mandates that a second-hit mutation and resulting loss of heterozygosity (LOH) of a tumor suppressor gene is necessary for tumor formation. LOH is commonly found in several types of hamartomas formed in the process of tuberous sclerosis, but not in brain lesions that contain characteristic giant cells.[6]

Hamartin and tuberin are believed to have a role in growth and differentiation of cells. Both proteins are found throughout the body and interact with each other. Little attention has been given to the recently discovered role of the TSC1/TSC2 complex in gene transcription via the Wnt signaling pathway; hamartin and tuberin have been found to modulate gene transcription via beta-catenin.[7]

Evidence also suggests that extracellular signal-regulated kinase (ERK) is specifically implicated in the pathogenesis of hamartomas.[8] Jozwiak et al postulate that ERK activation consistently detected in different tuberous sclerosis–associated tumors is a molecular trigger for the development of these neoplasms.[9] Cardiac rhabdomyoma arising in tuberous sclerosis may progress due to Erk potentiation.[10]

There are more than 450 different disease-causing mutations are known for TSC1 and more than 1300 for TSC2, with most of TSC1 mutations being truncating comprising frameshift, nonsense, and splice mutations.[11] A novel TSC2 mutation was recently described.[12] TSC2 -deficient cells may have increased choline phospholipid metabolism.[13]

Molecular studies suggest that tumor development relies on second-hit events, ie, a storm of them, to produce multifocal renal cell carcinoma in tuberous sclerosis complex.[14]




United States

Tuberous sclerosis complex affects approximately 40,000 people in the United States. The incidence is estimated to be 1 case per 6000 live births, with a prevalence of 1 in 10,000 births. The prevalence of tuberous sclerosis complex was previously estimated to be 1 in 50,000-100,000 births. Revision of the diagnostic criteria and improved recognition of the disease complex by physicians have resulted in an increased prevalence rate. Further evaluation of family members may also result in recognition of tuberous sclerosis complex in people with less severe phenotypes, which also increases the prevalence rate.


Estimates indicate that 2,000,000 people have tuberous sclerosis complex worldwide.

Mutations in the genes TSC1 or TSC2 had been considered rare in Korean populations. However, that may not be the case, as demonstrated by direct sequencing followed by multiplex ligation–dependent probe amplification analysis.[15]

Based on a meta-analysis of 380 tuberous sclerosis patients, the frequency of TSC1 mutations was found to be twice as high in the American and British populations compared with those from Poland and from the Republic of China.[16] These data should be verified with additional larger studies.


Overall, the most common cause of death in patients with tuberous sclerosis complex is status epilepticus or bronchopneumonia. The next most frequent cause of death is renal failure. Lymphangioleiomyomatosis (LAM) is the most common cause of death in patients with tuberous sclerosis complex, when present.

Morbidity is associated in the following organ systems:


Seizures, hydrocephalus, mental retardation, and autism or pervasive developmental disorder (PDD) are commonly associated with morbidity in children with tuberous sclerosis complex.

Seizures are the most common cause of morbidity and affect more than one half of patients with tuberous sclerosis complex. Infantile spasms affect approximately one third of patients and are often one of the early symptoms of tuberous sclerosis complex. An early age of onset of seizures is associated with risks of refractory seizures and decreased cognitive function. Earlier and more aggressive treatment may improve outcome

The growth of SEGAs may lead to hydrocephalus, although growth is gradual and patients often do not become symptomatic until significant hydrocephalus has developed. Patients may then experience neurologic sequelae, including blindness. Patients often require neurosurgery and shunt placement.

Approximately 50-85% of children with tuberous sclerosis complex have mental retardation. Approximately 0.1-0.7% of patients with mental retardation have tuberous sclerosis complex. Nearly all patients with mental retardation have seizures, although the reverse is not always true. Seizures and mental retardation may be concomitant.

Autism or PDD is present in 15-85% of children. The typical pattern of male bias in autism does not extend to patients with tuberous sclerosis complex.

Various behavioral disorders, including sleep disorders, hyperactivity, aggression, and schizophrenia, may be present in some individuals. Patients with tuberous sclerosis complex who have normal intelligence may be prone to developmental language disorders.


Various skin lesions are present in as many as 95% of patients with tuberous sclerosis complex. Facial angiofibromas, present in 75% of patients, cause the most morbidity because of the disfiguring cosmetic effects.


Approximately 70-80% of patients with tuberous sclerosis complex have either renal cysts, which are more common in children, or angiomyolipomas, which are more common in adults. Renal failure or hypovolemic shock due to bleeding angiomyolipomas may lead to death. Renal failure is the second most common cause of death in patients with tuberous sclerosis complex. The risk of bleeding increases when angiomyolipomas are larger than 4 cm. Rarely, renal lesions undergo differentiation to renal cell carcinoma.


Rhabdomyomas often develop at 22-26 weeks’ gestation. They may cause fetal death due to nonimmune hydrops fetalis. These benign tumors may cause valvular dysfunction, outflow obstruction in 1-2 ventricles, decreased contractility, and cardiomyopathy. Rhabdomyomas may also predispose patients to cardiac arrhythmias. In most patients, if outflow obstruction does not occur during the neonatal period, the lesions frequently resolve spontaneously or shrink after several years. Although cardiac rhabdomyomas are common, they do not usually cause mortality.


Lymphangioleiomyomatosis (LAM) predominantly occurs in females with tuberous sclerosis complex, although fewer than 1% of females are affected. Pulmonary hypertension and fibrosis may lead to cor pulmonale. Pneumothorax or pulmonary failure is often the final cause of death in patients with LAM or pulmonary cysts.


Tuberous sclerosis complex occurs with equal frequency in all races.


No sex predilection is noted in this autosomal dominant disease. Tuberous sclerosis complex in females tends to be associated with higher morbidity and mortality rates because the incidence of lung involvement is higher in females than in males.


Tuberous sclerosis complex is a congenital disorder, although age at diagnosis may range from birth to adulthood. Patients who are not severely affected may be diagnosed only when a family member is discovered to have tuberous sclerosis complex and all family members are evaluated. Younger patients typically present with cardiac rhabdomyomas, brain tumors, ash-leaf spots, or seizures, particularly infantile spasms. Diagnosis at a later age is often due to CNS and dermatologic manifestations.

Contributor Information and Disclosures

Robert A Schwartz, MD, MPH Professor and Head of Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, Rutgers New Jersey Medical School; Visiting Professor, Rutgers University School of Public Affairs and Administration

Robert A Schwartz, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, New York Academy of Medicine, American Academy of Dermatology, American College of Physicians, Sigma Xi

Disclosure: Nothing to disclose.


Robert Pedersen, MD Chief, Child Neurology, Tripler Army Medical Center; Clinical Professor, Pediatrics and Psychiatry, University of Hawaii, John A Burns School of Medicine

Robert Pedersen, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Pediatrics, Child Neurology Society

Disclosure: Nothing to disclose.

Sergiusz Jozwiak, MD, PhD Professor and Head of Pediatric Neurology, Warsaw Medical University, Poland

Sergiusz Jozwiak, MD, PhD is a member of the following medical societies: Sigma Xi

Disclosure: Received honoraria from Novartis for speaking and teaching.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Chief Editor

Luis O Rohena, MD Chief, Medical Genetics, San Antonio Military Medical Center; Assistant Professor of Pediatrics, Uniformed Services University of the Health Sciences, F Edward Hebert School of Medicine; Assistant Professor of Pediatrics, University of Texas Health Science Center at San Antonio

Luis O Rohena, MD is a member of the following medical societies: American Academy of Pediatrics, American Chemical Society, American College of Medical Genetics and Genomics, American Society of Human Genetics

Disclosure: Nothing to disclose.

Additional Contributors

Erawati V Bawle, MD, FAAP, FACMG Retired Professor, Department of Pediatrics, Wayne State University School of Medicine

Erawati V Bawle, MD, FAAP, FACMG is a member of the following medical societies: American College of Medical Genetics and Genomics, American Society of Human Genetics

Disclosure: Nothing to disclose.


The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous author, Christine Johnson, MD, to the development and writing of this article.

  1. Borkowska J, Schwartz RA, Jozwiak S. Recent perspectives on diagnosis and treatment of tuberous sclerosis complex in children. Int J Disability Human Development. 2009. 8:369-375.

  2. Crino PB, Henske EP. New developments in the neurobiology of the tuberous sclerosis complex. Neurology. 1999 Oct 22. 53(7):1384-90. [Medline].

  3. Borkowska J, Schwartz RA, Kotulska K, Jozwiak S. Tuberous sclerosis complex: tumors and tumorigenesis. Int J Dermatol. 2011 Jan. 50(1):13-20. [Medline].

  4. Krishnan ML, Commowick O, Jeste SS, et al. Diffusion features of white matter in tuberous sclerosis with tractography. Pediatr Neurol. 2010 Feb. 42(2):101-6. [Medline]. [Full Text].

  5. Jozwiak J. Hamartin and tuberin: working together for tumour suppression. Int J Cancer. 2006 Jan 1. 118(1):1-5. [Medline].

  6. Jozwiak J, Jozwiak S. Giant cells: contradiction to two-hit model of tuber formation?. Cell Mol Neurobiol. 2005 Aug. 25(5):795-805. [Medline].

  7. Jozwiak J, Wlodarski P. Hamartin and tuberin modulate gene transcription via beta-catenin. J Neurooncol. 2006 Sep. 79(3):229-34. [Medline].

  8. Jozwiak J, Grajkowska W, Kotulska K, Jozwiak S, Zalewski W, Zajaczkowska A. Brain tumor formation in tuberous sclerosis depends on Erk activation. Neuromolecular Med. 2007. 9(2):117-27. [Medline].

  9. Jozwiak J, Jozwiak S, Wlodarski P. Possible mechanisms of disease development in tuberous sclerosis. Lancet Oncol. 2008 Jan. 9(1):73-9. [Medline].

  10. Jozwiak J, Sahin M, Jozwiak S, et al. Cardiac rhabdomyoma in tuberous sclerosis: hyperactive Erk signaling. Int J Cardiol. 2009 Feb 6. 132(1):145-7. [Medline].

  11. Mayer K, Fonatsch C, Wimmer K, van den Ouweland AM, Maat-Kievit AJ. Clinical utility gene card for: Tuberous sclerosis complex (TSC1, TSC2). Eur J Hum Genet. 2013 Jun 12. [Medline].

  12. Yu Z, Zhang X, Guo H, et al. A novel TSC2 mutation in a Chinese family with tuberous sclerosis complex. J Genet. 2014 Apr. 93(1):169-72. [Medline].

  13. Priolo C, Ricoult SJ, Khabibullin D, et al. TSC2 Loss Increases Lysophosphatidylcholine Synthesis in Lymphangioleiomyomatosis. Am J Respir Cell Mol Biol. 2015 Mar 17. [Medline].

  14. Tyburczy ME, Jozwiak S, Malinowska IA, et al. A shower of second hit events as the cause of multifocal renal cell carcinoma in tuberous sclerosis complex. Hum Mol Genet. 2015 Apr 1. 24(7):1836-42. [Medline].

  15. Jang MA, Hong SB, Lee JH, Lee MH, Chung MP, Shin HJ, et al. Identification of TSC1 and TSC2 Mutations in Korean Patients With Tuberous Sclerosis Complex. Pediatr Neurol. 2012 Apr. 46(4):222-4. [Medline].

  16. Józwiak J, Sontowska I, Ploski R. Frequency of TSC1 and TSC2 mutations in American, British, Polish and Taiwanese populations. Mol Med Rep. 2013 Sep. 8(3):909-13. [Medline].

  17. Grajkowska W, Kotulska K, Jurkiewicz E, Matyja E. Brain lesions in tuberous sclerosis complex. Review. Folia Neuropathol. 2010. 48(3):139-49. [Medline].

  18. Jozwiak S, Schwartz RA, Janniger CK, Michalowicz R, Chmielik J. Skin lesions in children with tuberous sclerosis complex: their prevalence, natural course, and diagnostic significance. Int J Dermatol. 1998 Dec. 37(12):911-7. [Medline].

  19. Schwartz RA, Fernandez G, Kotulska K, Jozwiak S. Tuberous sclerosis complex: advances in diagnosis, genetics, and management. J Am Acad Dermatol. 2007 Aug. 57(2):189-202. [Medline].

  20. Rama Rao GR, Krishna Rao PV, Gopal KV, Kumar YH, Ramachandra BV. Forehead plaque: a cutaneous marker of CNS involvement in tuberous sclerosis. Indian J Dermatol Venereol Leprol. 2008 Jan-Feb. 74(1):28-31. [Medline].

  21. Quist SR, Franke I, Sutter C, Bartram CR, Gollnick HP, Leverkus M. Periungual fibroma (Koenen tumors) as isolated sign of tuberous sclerosis complex with tuberous sclerosis complex 1 germline mutation. J Am Acad Dermatol. 2010 Jan. 62(1):159-61. [Medline].

  22. Ma D, Darling T, Moss J, Lee CC. Histologic variants of periungual fibromas in tuberous sclerosis complex. J Am Acad Dermatol. 2011 Feb. 64(2):442-4. [Medline]. [Full Text].

  23. Moudouni SM, Tligui M, Sibony M, Doublet JD, Haab F, Gattegno B. Malignant epithelioid renal angiomyolipoma involving the inferior vena cava in a patient with tuberous sclerosis. Urol Int. 2008. 80(1):102-4; discussion 104. [Medline].

  24. Jozwiak S, Domanska-Pakiela D, Kwiatkowski DJ, Kotulska K. Multiple cardiac rhabdomyomas as a sole symptom of tuberous sclerosis complex: case report with molecular confirmation. J Child Neurol. 2005 Dec. 20(12):988-9. [Medline].

  25. Martignoni G, Pea M, Reghellin D, et al. Molecular pathology of lymphangioleiomyomatosis and other perivascular epithelioid cell tumors. Arch Pathol Lab Med. 2010 Jan. 134(1):33-40. [Medline].

  26. Sparling JD, Hong CH, Brahim JS, Moss J, Darling TN. Oral findings in 58 adults with tuberous sclerosis complex. J Am Acad Dermatol. 2007 May. 56(5):786-90. [Medline].

  27. Hasselblatt M, Jozwiak J, Mayer K, et al. Hypothalamic papillary tumor in a patient with tuberous sclerosis. Am J Surg Pathol. 2008 Oct. 32(10):1578-80. [Medline].

  28. McMaster ML, Goldstein AM, Parry DM. Clinical features distinguish childhood chordoma associated with tuberous sclerosis complex (TSC) from chordoma in the general paediatric population. J Med Genet. 2011 Jan 25. [Medline].

  29. Hyman MH, Whittemore VH. National Institutes of Health consensus conference: tuberous sclerosis complex. Arch Neurol. 2000 May. 57(5):662-5. [Medline].

  30. [Guideline] Roach ES, Sparagana SP. Diagnosis of tuberous sclerosis complex. J Child Neurol. 2004 Sep. 19(9):643-9. [Medline].

  31. Jozwiak S, Schwartz RA, Janniger CK, Bielicka-Cymerman J. Usefulness of diagnostic criteria of tuberous sclerosis complex in pediatric patients. J Child Neurol. 2000 Oct. 15(10):652-9. [Medline].

  32. Rok P, Kasprzyk-Obara J, Domanska-Pakiela D, Jozwiak S. Clinical symptoms of tuberous sclerosis complex in patients with an identical TSC2 mutation. Med Sci Monit. 2005 May. 11(5):CR230-234. [Medline].

  33. Staley BA, Vail EA, Thiele EA. Tuberous sclerosis complex: diagnostic challenges, presenting symptoms, and commonly missed signs. Pediatrics. 2011 Jan. 127(1):e117-25. [Medline]. [Full Text].

  34. Huggins RH, Janusz CA, Schwartz RA. Vitiligo: a sign of systemic disease. Indian J Dermatol Venereol Leprol. 2006 Jan-Feb. 72(1):68-71. [Medline].

  35. Arva NC, Pappas JG, Bhatla T, Raetz EA, Macari M, Ginsburg HB, et al. Well-differentiated pancreatic neuroendocrine carcinoma in tuberous sclerosis--case report and review of the literature. Am J Surg Pathol. 2012 Jan. 36(1):149-53. [Medline].

  36. Jurkiewicz E, Jozwiak S, Bekiesinska-Figatowska M, Pakula-Kosciesza I, Walecki J. Cyst-like cortical tubers in patients with tuberous sclerosis complex: MR imaging with the FLAIR sequence. Pediatr Radiol. 2006 Jun. 36(6):498-501. [Medline].

  37. Jozwiak J, Jozwiak S, Oldak M. Molecular activity of sirolimus and its possible application in tuberous sclerosis treatment. Med Res Rev. 2006 Mar. 26(2):160-80. [Medline].

  38. Paghdal KV, Schwartz RA. Sirolimus (rapamycin): from the soil of Easter Island to a bright future. J Am Acad Dermatol. 2007 Dec. 57(6):1046-50. [Medline].

  39. Davies DM, Johnson SR, Tattersfield AE, Kingswood JC, Cox JA, McCartney DL. Sirolimus therapy in tuberous sclerosis or sporadic lymphangioleiomyomatosis. N Engl J Med. 2008 Jan 10. 358(2):200-3. [Medline].

  40. Krueger DA, Care MM, Holland K, et al. Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis. N Engl J Med. 2010 Nov 4. 363(19):1801-11. [Medline].

  41. Hauptman JS. From the bench to the bedside: Everolimus for subependymal giant cell astrocytomas in Tuberous sclerosis complex, optic nerve regeneration, targeted cytotoxins for gliomas. Surg Neurol Int. 2011 Jan 14. 2:2. [Medline]. [Full Text].

  42. Nawashiro H, Shinomiya N. Everolimus and giant-cell astrocytomas in tuberous sclerosis. N Engl J Med. 2011 Feb 10. 364(6):576-7. [Medline].

  43. Perek-Polnik M, Józwiak 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. 2012 Jan. 16(1):83-5. [Medline].

  44. Józwiak S, Kotulska K, Domanska-Pakiela D, Lojszczyk B, Syczewska M, Chmielewski D, 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. 2011 Sep. 15(5):424-31. [Medline].

  45. Wu JY, Salamon N, Kirsch HE, et al. Noninvasive testing, early surgery, and seizure freedom in tuberous sclerosis complex. Neurology. 2010 Feb 2. 74(5):392-8. [Medline]. [Full Text].

  46. Matsuyama K, Ohsawa I, Ogawa T. Do children with tuberous sclerosis complex have superior musical skill? - A unique tendency of musical responsiveness in children with TSC. Med Sci Monit. 2007 Mar 27. 13(4):CR156-164. [Medline].

  47. Kingswood JC, Jozwiak S, Belousova ED, Frost MD, Kuperman RA, Bebin EM, 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. 2014 Jun. 29(6):1203-10. [Medline].

  48. Roth J, Roach ES, Bartels U, Józwiak S, Koenig MK, Weiner HL, et al. Subependymal giant cell astrocytoma: diagnosis, screening, and treatment. Recommendations from the International Tuberous Sclerosis Complex Consensus Conference 2012. Pediatr Neurol. 2013 Dec. 49(6):439-44. [Medline].

  49. Trelinska J, Dachowska I, Kotulska K, 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. 2015 Apr. 26(4):437-42. [Medline].

  50. Brodie MJ. Lamotrigine--an update. Can J Neurol Sci. 1996 Nov. 23(4):S6-9. [Medline].

  51. Brodie MJ, Dichter MA. Antiepileptic drugs. N Engl J Med. 1996 Jan 18. 334(3):168-75. [Medline].

  52. Kaczorowska M, Jurkiewicz E, Domanska-Pakiela D, et al. Cerebral tuber count and its impact on mental outcome of patients with tuberous sclerosis complex. Epilepsia. 2011 Jan. 52(1):22-7. [Medline].

  53. Pressey JG, Wright JM, Geller JI, Joseph DB, Pressey CS, Kelly DR. Sirolimus therapy for fibromatosis and multifocal renal cell carcinoma in a child with tuberous sclerosis complex. Pediatr Blood Cancer. 2010 Jan 27. [Medline].

  54. Curatolo P, Bombardieri R, Jozwiak S. Tuberous sclerosis. Lancet. 2008 Aug 23. 372(9639):657-68. [Medline].

  55. Dabora SL, Jozwiak S, Franz DN, 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. 2001 Jan. 68(1):64-80. [Medline].

  56. de Vries PJ, Watson P. Attention deficits in tuberous sclerosis complex (TSC): rethinking the pathways to the endstate. J Intellect Disabil Res. 2007 Dec 19. [Medline].

  57. Dichter MA, Brodie MJ. New antiepileptic drugs. N Engl J Med. 1996 Jun 13. 334(24):1583-90. [Medline].

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

  59. Haslam RH. Nonfebrile seizures. Pediatr Rev. 1997 Feb. 18(2):39-49. [Medline].

  60. Hoogeveen-Westerveld M, Wentink M, van den Heuvel D, et al. Functional assessment of variants in the TSC1 and TSC2 genes identified in individuals with Tuberous Sclerosis Complex. Hum Mutat. 2011 Feb 1. [Medline].

  61. Hurst JS, Wilcoski S. Recognizing an index case of tuberous sclerosis. Am Fam Physician. 2000 Feb 1. 61(3):703-8, 710. [Medline].

  62. Husain AM, Foley CM, Legido A, et al. Tuberous sclerosis complex and epilepsy: prognostic significance of electroencephalography and magnetic resonance imaging. J Child Neurol. 2000 Feb. 15(2):81-3. [Medline].

  63. Jozwiak J, Galus R. Molecular implications of skin lesions in tuberous sclerosis. Am J Dermatopathol. 2008 Jun. 30(3):256-61. [Medline].

  64. Jozwiak J, Kotulska K, Lojek M, et al. Fibroblasts from normal skin of a tuberous sclerosis patient show upregulation of mTOR pathway. Am J Dermatopathol. 2009 Feb. 31(1):68-70. [Medline].

  65. Jozwiak J, Sahin M, Jozwiak S, et al. Cardiac rhabdomyoma in tuberous sclerosis: Hyperactive Erk signaling. Int J Cardiol. 2007 Nov 23. [Medline].

  66. Jozwiak S, Domanska-Pakiela D, Kotulska K, Kaczorowska M. Treatment before seizures: new indications for antiepileptic therapy in children with tuberous sclerosis complex. Epilepsia. 2007 Aug. 48(8):1632; author reply 1632-4. [Medline].

  67. Jozwiak S, Kotulska K, Kasprzyk-Obara J, Domanska-Pakiela D, Tomyn-Drabik M, Roberts P. Clinical and genotype studies of cardiac tumors in 154 patients with tuberous sclerosis complex. Pediatrics. 2006 Oct. 118(4):e1146-51. [Medline].

  68. Jurkiewicz E, Jozwiak S. Giant intracranial aneurysm in a 9-year-old boy with tuberous sclerosis. Pediatr Radiol. 2006 May. 36(5):463. [Medline].

  69. Korf BR. Neurocutaneous syndromes: neurofibromatosis 1, neurofibromatosis 2, and tuberous sclerosis. Curr Opin Neurol. 1997 Apr. 10(2):131-6. [Medline].

  70. Kothare SV, Singh K, Chalifoux JR, Staley BA, Weiner HL, Menzer K, et al. Severity of manifestations in tuberous sclerosis complex in relation to genotype. Epilepsia. 2014 Jul. 55(7):1025-9. [Medline].

  71. Kothare SV, Singh K, Hochman T, Chalifoux JR, Staley BA, Weiner HL, et al. Genotype/phenotype in tuberous sclerosis complex: associations with clinical and radiologic manifestations. Epilepsia. 2014 Jul. 55(7):1020-4. [Medline].

  72. Kotulska K, Borkowska J, Mandera M, Roszkowski M, Jurkiewicz E, Grajkowska W, et al. Congenital subependymal giant cell astrocytomas in patients with tuberous sclerosis complex. Childs Nerv Syst. 2014 Sep 17. [Medline].

  73. Krymskaya VP, Goncharova EA. PI3K/mTORC1 activation in hamartoma syndromes: Therapeutic prospects. Cell Cycle. 2009 Feb 6. 8(3):[Medline].

  74. Martin N, Debussche C, De Broucker T, et al. Gadolinium-DTPA enhanced MR imaging in tuberous sclerosis. Neuroradiology. 1990. 31(6):492-7. [Medline].

  75. Miller SP, Tasch T, Sylvain M, et al. Tuberous sclerosis complex and neonatal seizures. J Child Neurol. 1998 Dec. 13(12):619-23. [Medline].

  76. Monaghan HP, Krafchik BR, MacGregor DL, Fitz CR. Tuberous sclerosis complex in children. Am J Dis Child. 1981 Oct. 135(10):912-7. [Medline].

  77. Morse RP. Tuberous sclerosis. Arch Neurol. 1998 Sep. 55(9):1257-8. [Medline].

  78. Nakase Y, Fukuda K, Chikashige Y, et al. A defect in protein farnesylation suppresses a loss of Schizosaccharomyces pombe tsc2+, a homolog of the human gene predisposing to tuberous sclerosis complex. Genetics. 2006 Jun. 173(2):569-78. [Medline]. [Full Text].

  79. O'Hagan AR, Ellsworth R, Secic M, Rothner AD, Brouhard BH. Renal manifestations of tuberous sclerosis complex. Clin Pediatr (Phila). 1996 Oct. 35(10):483-9. [Medline].

  80. 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].

  81. Roach ES, Williams DP, Laster DW. Magnetic resonance imaging in tuberous sclerosis. Arch Neurol. 1987 Mar. 44(3):301-3. [Medline].

  82. Shepherd CW, Gomez MR, Lie JT, Crowson CS. Causes of death in patients with tuberous sclerosis. Mayo Clin Proc. 1991 Aug. 66(8):792-6. [Medline].

  83. Stefansson K. Tuberous sclerosis. Mayo Clin Proc. 1991 Aug. 66(8):868-72. [Medline].

  84. Wlodarski PK, Maksym R, Oldak M, Jozwiak S, Wojcik A, Jozwiak J. Tuberin-heterozygous cell line TSC2ang1 as a model for tuberous sclerosis-associated skin lesions. Int J Mol Med. 2008 Feb. 21(2):245-50. [Medline].

Facial angiofibroma, previously termed adenoma sebaceum, in a patient with tuberous sclerosis complex (TSC).
Forehead plaque in a patient with tuberous sclerosis complex (TSC). The presence of either a forehead plaque or a facial angiofibroma constitutes one of the major diagnostic criteria for TSC.
Ash-leaf spots are hypomelanotic lesions that are observed more easily with the use of a Wood lamp.
A shagreen patch is a connective tissue hamartoma with a leathery texture and is found most commonly in the lower back region.
Confetti skin lesions are hypomelanotic lesions that cluster and appear reticulated.
MRI in a patient with tuberous sclerosis complex (TSC) demonstrates the presence of a tuber and subependymal nodules.
Periungual fibroma on the thumb of a patient with tuberous sclerosis complex (TSC).
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