Genetics of Tuberous Sclerosis Treatment & Management
- Author: Robert A Schwartz, MD, MPH; Chief Editor: Luis O Rohena, MD more...
Medical care is aimed at seizure control using various anticonvulsants. Begin treatment with monotherapy and increase the dose gradually until seizures are well controlled or the dose is limited by adverse effects. If the first drug is ineffective, try a different anticonvulsant agent while the first drug is gradually weaned, rather than directly initiating multidrug therapy. A second anticonvulsant may be added if monotherapy with various medications fails. Treatment is desirable before seizures, representing new indications for antiepileptic therapy in children with tuberous sclerosis complex (TSC).
Lymphangioleiomyomatosis (LAM) may respond to therapy using progesterone and oophorectomy. Therefore, treatment in females with evidence of pulmonary disease should begin with progesterone.
Consider inotropic agents in patients with evidence of decreased contractility and cardiomyopathy due to rhabdomyoma.
Antihypertensive medication may be required in patients with renal disease and subsequent hypertension. An ACE inhibitor may be the first drug of choice. For more information, see the topic Hypertension in the Pediatric Cardiac Disease and Critical Care Medicine Volume.
Rapamycin (sirolimus) may be useful in tuberous sclerosis treatment. It binds to its intracellular receptor, FK506-binding protein 12 (FKBP12), and inhibits the activity of the mammalian target of rapamycin (mTOR), a serine/threonine kinase involved in numerous cell processes linked to cell growth control. Investigational studies with sirolimus and everolimus are in progress.[38, 19, 39, 40, 41, 42] Successful everolimus treatment of a huge subependymal giant cell astrocytoma in a 10-year old boy with TSC has been described. Everolimus treatment may be a therapeutic option alternative to surgery.
Preventative antiepileptic treatment of 45 infants with TSC and high risk of epilepsy was found to markedly improve neurodevelopmental outcome and reduce the incidence of drug-resistant seizures.
Anticonvulsant medication is the first treatment option, and neurosurgery is rarely required for refractory seizures. The best outcome has been noted in patients with fewer lesions. MRI, EEG, and positron emission tomography (PET) scans to localize the lesions are important prior to neurosurgery. Growth of subependymal giant cell astrocytomas (SEGAs) may result in increased intracranial pressure and hydrocephalus. People with increased intracranial pressure require immediate surgery to remove the obstructing lesions. Ventriculoperitoneal (VP) shunt placement is sometimes required.
However, magnetic source imaging and (18)fluorodeoxyglucose PET/MRI coregistration may be able to noninvasively localize the epileptogenic zones in many children with tuberous sclerosis complex and intractable epilepsy, with a 67% seizure-free rate postoperatively. Some believe that early epilepsy surgery is associated with seizure freedom in children with tuberous sclerosis complex and intractable epilepsy.
Partial nephrectomy, enucleation, or renal arterial embolization: Angiomyolipomas may progress and lead to renal failure or bleeding, with resultant hemorrhagic shock. In general, any symptomatic lesion or a lesion larger than 3.5-4 cm should be closely monitored, and surgical treatment should be considered. The goal of surgical treatment is to spare the kidneys as much as possible because new lesions may develop in the future. Therefore, surgical treatment usually consists of enucleation or partial nephrectomy. Renal arterial embolization is an additional treatment option.
Oophorectomy and progesterone therapy are believed to have a beneficial impact on LAM in females. In individuals with end-stage lung disease, lung transplantation is sometimes performed, although it is not always successful.
Cardiac surgery for the removal of rhabdomyomas is rarely required but is performed when cardiac failure is caused by outflow obstruction. Cardiac rhabdomyomas usually spontaneously regress as the individual ages, thus obviating the need for cardiac surgery in older individuals.
Facial angiofibromas may require cosmetic therapy. Previously treated with dermal abrasion techniques, they are currently treated more successfully using laser therapy.
Consult with a neurosurgeon immediately if any suggestion or evidence of increased intracranial pressure is present. Surgery is required to relieve the obstruction and to reduce intracranial pressure. Neurosurgery is rarely required for treatment of epilepsy.
A neurologist may be consulted to assist with seizure management and anticonvulsant medication. In addition, a neurologist may assist with obtaining baseline and serial neurologic examinations to assess for neurologic deficits.
Consultation with a cardiologist is recommended so that initial and surveillance echocardiograms can be obtained to assess cardiac rhabdomyomas. Cardiac surgery is rarely required for removal of rhabdomyomas.
An ophthalmologist may perform a thorough funduscopic examination to assess for evidence of retinal hamartomas or astrocytomas.
Consultation with a genetic counselor is recommended when a child/adult is first diagnosed with tuberous sclerosis complex to review the natural history, inheritance, recurrence risks, and the possibility of molecular/genetic testing. The counselor spends adequate time to explain the above in nonmedical terms and may refer the family to other consumer resources. Genetic consultation is particularly helpful when parents of children with tuberous sclerosis complex are contemplating future pregnancies.
A pulmonologist may assist with management of LAM in females with tuberous sclerosis complex. Consult a nephrologist for individuals with symptomatic renal disease. Consultation with a neuropsychologist is helpful in assessing intellectual ability in a child with tuberous sclerosis complex. Neuropsychologists may also assist in management of various behavioral problems, such as autism or pervasive developmental disorder (PDD), schizophrenia, aggressive behavior, or sleep disturbances. Finally, a social worker may assist families and individuals in coping with this chronic disorder.
No specific diet is recommended for most patients.
A ketogenic diet is recommended for some patients for seizure control. Patient compliance with this diet may be difficult to obtain because of limited choices and unpleasant tastes. A ketogenic diet is most useful in patients who have seizures that are difficult to control using multidrug therapy.
A combination of a ketogenic diet and valproic acid is contraindicated because of the increased risk of hepatotoxicity.
Children with tuberous sclerosis complex show high responsiveness to musical stimuli despite otherwise delayed development in language, cognition, and motor skills. The use of music as therapeutic intervention has been suggested.
Activity is not restricted in patients with tuberous sclerosis complex who do not have a history of seizures.
Patients with a history of seizures should avoid certain activities, such as scuba diving and rock climbing.
Driving restrictions for people with seizures vary by state, and physicians should be aware of local regulations.
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.
Crino PB, Henske EP. New developments in the neurobiology of the tuberous sclerosis complex. Neurology. 1999 Oct 22. 53(7):1384-90. [Medline].
Borkowska J, Schwartz RA, Kotulska K, Jozwiak S. Tuberous sclerosis complex: tumors and tumorigenesis. Int J Dermatol. 2011 Jan. 50(1):13-20. [Medline].
Jozwiak J. Hamartin and tuberin: working together for tumour suppression. Int J Cancer. 2006 Jan 1. 118(1):1-5. [Medline].
Jozwiak J, Jozwiak S. Giant cells: contradiction to two-hit model of tuber formation?. Cell Mol Neurobiol. 2005 Aug. 25(5):795-805. [Medline].
Jozwiak J, Wlodarski P. Hamartin and tuberin modulate gene transcription via beta-catenin. J Neurooncol. 2006 Sep. 79(3):229-34. [Medline].
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].
Jozwiak J, Jozwiak S, Wlodarski P. Possible mechanisms of disease development in tuberous sclerosis. Lancet Oncol. 2008 Jan. 9(1):73-9. [Medline].
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].
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].
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].
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].
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].
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].
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].
Grajkowska W, Kotulska K, Jurkiewicz E, Matyja E. Brain lesions in tuberous sclerosis complex. Review. Folia Neuropathol. 2010. 48(3):139-49. [Medline].
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].
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].
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].
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].
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].
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].
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].
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].
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].
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].
Hyman MH, Whittemore VH. National Institutes of Health consensus conference: tuberous sclerosis complex. Arch Neurol. 2000 May. 57(5):662-5. [Medline].
[Guideline] Roach ES, Sparagana SP. Diagnosis of tuberous sclerosis complex. J Child Neurol. 2004 Sep. 19(9):643-9. [Medline].
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].
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].
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].
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].
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].
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].
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].
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].
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].
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].
Nawashiro H, Shinomiya N. Everolimus and giant-cell astrocytomas in tuberous sclerosis. N Engl J Med. 2011 Feb 10. 364(6):576-7. [Medline].
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].
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].
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].
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].
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].
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].
Brodie MJ. Lamotrigine--an update. Can J Neurol Sci. 1996 Nov. 23(4):S6-9. [Medline].
Brodie MJ, Dichter MA. Antiepileptic drugs. N Engl J Med. 1996 Jan 18. 334(3):168-75. [Medline].
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].
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].
Curatolo P, Bombardieri R, Jozwiak S. Tuberous sclerosis. Lancet. 2008 Aug 23. 372(9639):657-68. [Medline].
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].
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].
Dichter MA, Brodie MJ. New antiepileptic drugs. N Engl J Med. 1996 Jun 13. 334(24):1583-90. [Medline].
Franz DN. Diagnosis and management of tuberous sclerosis complex. Semin Pediatr Neurol. 1998 Dec. 5(4):253-68. [Medline].
Haslam RH. Nonfebrile seizures. Pediatr Rev. 1997 Feb. 18(2):39-49. [Medline].
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].
Hurst JS, Wilcoski S. Recognizing an index case of tuberous sclerosis. Am Fam Physician. 2000 Feb 1. 61(3):703-8, 710. [Medline].
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].
Jozwiak J, Galus R. Molecular implications of skin lesions in tuberous sclerosis. Am J Dermatopathol. 2008 Jun. 30(3):256-61. [Medline].
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].
Jozwiak J, Sahin M, Jozwiak S, et al. Cardiac rhabdomyoma in tuberous sclerosis: Hyperactive Erk signaling. Int J Cardiol. 2007 Nov 23. [Medline].
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].
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].
Jurkiewicz E, Jozwiak S. Giant intracranial aneurysm in a 9-year-old boy with tuberous sclerosis. Pediatr Radiol. 2006 May. 36(5):463. [Medline].
Korf BR. Neurocutaneous syndromes: neurofibromatosis 1, neurofibromatosis 2, and tuberous sclerosis. Curr Opin Neurol. 1997 Apr. 10(2):131-6. [Medline].
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].
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].
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].
Krymskaya VP, Goncharova EA. PI3K/mTORC1 activation in hamartoma syndromes: Therapeutic prospects. Cell Cycle. 2009 Feb 6. 8(3):[Medline].
Martin N, Debussche C, De Broucker T, et al. Gadolinium-DTPA enhanced MR imaging in tuberous sclerosis. Neuroradiology. 1990. 31(6):492-7. [Medline].
Miller SP, Tasch T, Sylvain M, et al. Tuberous sclerosis complex and neonatal seizures. J Child Neurol. 1998 Dec. 13(12):619-23. [Medline].
Monaghan HP, Krafchik BR, MacGregor DL, Fitz CR. Tuberous sclerosis complex in children. Am J Dis Child. 1981 Oct. 135(10):912-7. [Medline].
Morse RP. Tuberous sclerosis. Arch Neurol. 1998 Sep. 55(9):1257-8. [Medline].
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].
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].
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].
Roach ES, Williams DP, Laster DW. Magnetic resonance imaging in tuberous sclerosis. Arch Neurol. 1987 Mar. 44(3):301-3. [Medline].
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].
Stefansson K. Tuberous sclerosis. Mayo Clin Proc. 1991 Aug. 66(8):868-72. [Medline].
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].