What is TSC?
Tuberous sclerosis complex (TSC), is a rare genetic disease that causes benign (non-cancerous) tumours to grow in different areas of the body, most commonly the brain, kidneys, skin, heart, and lungs. The severity of the condition can vary widely and affects everybody differently. In some people the disease is very mild, while others may have serious manifestations. It is a progressive disease, and symptoms emerge and change through the person’s lifetime.
There is no cure, and treatment relies on symptom management for which there are international clinical consensus recommendations. Considerable progress has been made in treatments in recent years and the prognosis of somebody with TSC is continuously improving. TSC has a global live birth prevalence of approximately 1:6000-1:10000.
Receiving a diagnosis of Tuberous Sclerosis Complex (TSC) may be overwhelming for you and your family. We hope this website & booklet, compiled by parents of children with TSC, and healthcare professionals, will help you through this difficult time.
Signs, Symptoms & Management of Tuberous Sclerosis Complex (TSC)
TSC affects no two people in the same way. They may experience physical/ psychiatric/ and/or psycholgical symptoms, ranging from mild to severe. There is no way predict with certainty how the disorder will manifest and progress.
The diagnosis of TSC can be made based on clinical manifestations or genetic testing. However, genetic testing is recommended in all cases, and accurate diagnosis is critical to the surveillance and management of the disease. International consensus recommendations for the diagnosis, surveillance, and management of TSC exist.
Below are the consensus clinical diagnostic, surveillance & management guidelines for the physical and Tuberous Sclerosis Associated Neuropsychiatric (TAND) symptoms.
Many different organs potentially affected by TSC are listed below. To learn about how an organ can be affected by TSC, click on the organs below. For Information about Tuberous Sclerosis Neuropsychiatric Disorders (TAND), there is a specific section below and direct link.
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Several different types of brain lesions are seen in individuals with TSC: Cortical tubers, subependymal nodules (SEN) and subependymal giant cell astrocytoma (SEGAs). Some people will have some of the lesions and others all the lesions, whereas others will have no brain involvement at all.
Brain imaging should be done at the time of diagnosis to get a baseline image and then according to International Consensus Guidelines, (usually every 1 to 3 years afterward).
The most common effects of these brain manifestation are epilepsy or seizures occurring in approximately 85% of individuals diagnosed with TSC and Tuberous Sclerosis Complex Neuropsychiatric disorders (TAND) occurring in over 90%.
Cortical Tubers (from which TSC is named) can be thought of as a “birth defect” on the brain. ‘Tuber’ is Latin for swelling and ‘skleros’ is Greek for hard. Cortical tubers are found in 80-90% of persons with TSC. They are small areas in the cortex (the outer layer of the brain) that do not develop normally and contain abnormal brain cells. Tubers can be seen as early as 20 weeks’ gestation and the number of tubers in the brain of individuals with TSC stays the same throughout their life. Tubers are best seen by magnetic resonance imaging (MRI). It is thought that the presence of cortical tubers, and subsequent changes in the areas around them, disrupts the normal “wiring” of the brain and causes seizures in individuals with TSC.
Subependymal nodules (SENs) Subependymal nodules (SEN) are groups of cells forming nodules < 1 cm, found on the walls of the cerebral ventricles (the natural cavities in the brain which contain cerebrospinal fluid CSF) and seen in 80% of TSC patients. They are visible within the first 6 months of life and are frequently asymptomatic. SENs are also non-cancerous. They grow in proportion to the tissue around them and can calcify with age. However, in 20% of patients they may develop into subependymal giant cell astrocytoma (SEGAs) and can cause serious complications. They are not believed to be directly responsible for neurological problems. The word ‘subependymal’ refers to their location below the ependyma (the membrane lining the ventricles inside the brain).
SENs can by identified using magnetic Resonance Imaging (MRI). If SENs have calcified with age, they can be easily detected with a computed tomography (CT) scan.
Subependymal giant cell astrocytomas (SEGAs). Subependymal giant cell astrocytomas (SEGAs) develop in up to 20% individuals with TSC. Typically, SEGAs do not occur in very young children but grow during childhood with the chance for their growth decreasing after 20 years of age.
SEGAs are found in the lining of the ventricles in the brain. Ventricles are natural spaces inside the brain filled with a clear fluid called cerebrospinal fluid (CSF). SEGAs are non-cancerous, however, they can be problematic because they may grow large enough to block the flow of CSF within the brain. This causes increased pressure within the brain (hydrocephalus) and people with TSC can become very unwell and require surgical intervention. Symptoms of hydrocephalus include vomiting, nausea, and headaches as well as changes in appetite, behaviour, and mood. These symptoms may or may not signal growth of a SEGA but indicate that there may be a problem and that the patient should be seen by a physician.
Note: Epilepsy/seizures and Tuberous Sclerosis Complex Neuropsychiatric disorders (TAND) which include behavioural, psychiatric, intellectual, learning, neuropsychological and psychiatric challenges, are dealt with in separate sections below.
Last updated on 04/04/2026
References
Crino P.B., Aronica E., Baltuch G., Nathanson K.L. Biallelic TSC gene inactivation in tuberous sclerosis complex. Neurology. 2010;74:1716–1723. doi: 10.1212/WNL.0b013e3181e04325.
Franz DN, Belousova E, Sparagana S, et al. (2013) 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.
French J.A., Lawson J.A., Yapici Z., Ikeda H., Polster T., Nabbout R., Curatolo P., de Vries P.J., Dlugos D.J., Berkowitz N., et al. Adjunctive everolimus therapy for treatment-resistant focal-onset seizures associated with tuberous sclerosis (EXIST-3): A phase 3, randomised, double-blind, placebo-controlled study. Lancet. 2016;388:2153–2163. doi: 10.1016/S0140-6736(16)31419-2.
Gomez M.R. Definition and criteria for diagnosis. In: Gomez M.R., Sampson J.R., Whittemore V.H., editors. Tuberous Sclerosis Complex. 3rd ed. Oxford University Press; New York, NY, USA: 1999. pp. 10–23.
Gomez M.R. Natural history of cerebral tuberous sclerosis. In: Gomez M.R., Sampson J.R., Whittemore V.H., editors. Tuberous Sclerosis Complex. 3rd ed. Oxford University Press; New York, NY, USA: 1999. pp. 29–46.i
Jansen AC et al Clinical Characteristics of Subependymal Giant Cell Astrocytoma in Tuberous Sclerosis Complex. Front Neurol. 2019 Jul 3;10:705. doi: 10.3389/fneur.2019.00705. PMID: 31333563; PMCID: PMC6616060.
Kwiatkowski D.J., Whittemore V.H. & Thiele E.A. (2010) Tuberous Sclerosis Complex: Genes, Clinical Features, and Therapeutics. Weinheim: Wiley-Blackwell
Lu DS, Patrick, Karas J, Krueger DA, Weiner HL. Central nervous system manifestations of tuberous sclerosis complex. American Journal of Medical Genetics. 2018(178C):291-8.
Mizuguchi M, Ohsawa M, Kashii H, Sato A. Brain Symptoms of Tuberous Sclerosis Complex: Pathogenesis and Treatment. Int J Mol Sci. 2021 Jun 22;22(13):6677. doi: 10.3390/ijms22136677. PMID: 34206526; PMCID: PMC8268912.Brain Symptoms of Tuberous Sclerosis Complex: Pathogenesis and Treatment
Northrup, H. et al. Updated international tuberous sclerosis complex diagnostic criteria and surveillance and management recommendations. Pediatr. Neurol. 123, 50–66 (2021). This reports the latest international consensus recommendations for the diagnosis and management of TSC.
Winden, K., Bebin, E.M., Jeste, S. et al. Tuberous sclerosis complex. Nat Rev Dis Primers 12, 11 (2026).
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Epilepsy is derived from the Greek word ‘epilambanein’ and means to be seized or overwhelmed by surprise. A ‘seizure’ is caused by the hyper-synchronous discharge of nerve cells (abnormal, excessive synchronization of electrical activity among a large population of neurons) in the brain causing an alteration of neurological function. Epilepsy describes that an individual has epileptic seizure and the brain displays ‘a pathological and enduring tendency to have recurrent seizures’.
Epilepsy occurs in about 90% of persons with TSC . All seizure types such as tonic, atonic, tonic-clonic, focal or generalised can be seen in patients with TSC and can begin any time from childhood into adulthood. Focal seizures are the most common seizure type seen in TSC patients and observed in 67.5% and it is known that up to 12% of patients with TSC can develop epilepsy as adults. Infantile spasms (IS) are encountered in 38.9% of cases.
About two thirds of TSC patients are reported to develop refractory epilepsy (drug resistant epilepsy) which is associated with intellectual disability and neuropsychiatric disorders known as Tuberous Sclerosis Associated Neuropsychiatric Disorders (TAND).
There are several therapeutic options available for the treatment of all epilepsy types, including antiepileptic drugs (AEDs), hormonal treatment, ketogenic diet, epilepsy surgery and vagus nerve stimulation and more recently, the use of mTOR inhibitors.
In TSC patients, epilepsy is often observed in the first months of life and in most cases within the first two years. At this age, epilepsy usually presents as focal seizures with or without infantile spasms. Study have found that the age at onset of seizures and overall seizure burden in the first years of life were more predictive of developmental outcomes than the presence of infantile spasms
It is crucial to recognise seizures at an early stage in order to commence antiepileptic treatment and improve long-term outcomes and reduce intellectual disability.
Epilepsy Ireland offers information and a wide range of services to support people with epilepsy.
Visit Tuberous Sclerosis Australia for information on the different types of seizures
Infantile spasms (IS) are a medical emergency. They are a serious type of seizure occurring in infancy which can cause catastrophic and permanent damage to a child’s brain. IS last around one to two seconds in a series and more often after waking up. They include repetitive but often subtle movements – including jerking of the mid-section, dropping of the head, raising of the arms or wide-eyed blinks. Unfortunately, infantile spasms can often be overlooked or misdiagnosed for other conditions, including colic, reflux, or a startle reflex.In 90% of cases, they occur in infants less than 12 months of age and are more usually diagnosed between four and eight months, however, they can occur up to 2 years of age. The presence of infantile spasms can be an early indicator of TSC and are a common neurological manifestation of TSC and it is estimated that up to 50% of infants experience them. Outcomes can vary dependent on the promptness of identifying the spasms and prioritising treatment. Global delays across learning and development as well as specific learning and developmental difficulties can be an impact of the spasms, which is why it is so important to have an early diagnosis and to start treatment immediately.
Please see this important video:Infantile Spasms: What Every Parent Needs To Know
Last updated on 05/04/2026.
References
Capal, J. K. et al. Influence of seizures on early development in tuberous sclerosis complex. Epilepsy Behav. 70, 245–252 (2017
Chu-Shore CJ, Major P, Camposano S, Muzykewicz D, Thiele EA. The natural history of epilepsy in tuberous sclerosis complex. Epilepsia. 2009;51(7):1236-41.
Curatolo P, Moavero R, de Vries PJ. Neurological and neuropsychiatric aspects of tuberous sclerosis complex. Lancet Neurology. 2015;14(7):733-45.
Fisher RS, Acevedo C, Arzimanoglou A, Bogacz A, Cross JH, Elger CE, et al. ILAE official report: A practical clinical definition of epilepsy. Epilepsia. 2014;55(4):475-82.
Jozwiak S, Curatolo P. Editorial: Tuberous sclerosis complex - diagnosis and management. Frontiers in Neurology. 2021;12:755868.
Jozwiak S, Kotulska K, Wong M, Bebin M. Modifying genetic epilepsies - Results from studies on tuberous sclerosis complex. Neuropharmacology. 2020;166:107908.
Kingswood C, Bolton P, Crawford P, Harland C, Johnson SR, Sampson JR, 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). European Journal of Paediatric Neurology. 2016;20(2):296-308.
Kingswood JC, d'Augeres GB, Belousova E, Ferreira JC, Carter T, Castellana R, et al. TuberOus SClerosis registry to increase disease Awareness (tosca) - baseline data on 2093 patients. Orphanet Journal of Rare Diseases. 2017;12(1):2.
Kingswood JC, Bruzzi P, Curatolo P, De Vries PJ, Fladrowski C, Hertzberg C, et al. TOSCA – first international registry to address knowledge gaps in the natural history and management of tuberous sclerosis complex. Orphanet Journal of Rare Diseases. 2014;9(1):182.
Luo C, Ye W-R, Shi W, Yin P, Chen C, He Y-B, et al. Perfect match: mtor inhibitors and tuberous sclerosis complex. Orphanet Journal of Rare Diseases. 2022;17(1):16.
Moloney PB, Behan C, Doherty CP, Costello DJ, El-Naggar H, Delanty N. Everolimus for drug-resistant seizures in tuberous sclerosis complex: an Irish experience. Irish Journal of Medical Science. 2022;191:S71
Nabbout R, Belousova E, Benedik MP, Carter T, Cottin V, Curatolo P, et al. Epilepsy in tuberous sclerosis complex: Findings from the tosca Study. Epilepsia Open. 2019;4:73-84.
Northrup, H. et al. Updated international tuberous sclerosis complex diagnostic criteria and surveillance and management recommendations. Pediatr. Neurol. 123, 50–66 (2021). This reports the latest international consensus recommendations for the diagnosis and management of TSC.
Shepherd C, Koepp M, Myland M, Patel K, Miglio C, Siva V, et al. Understanding the health economic burden of patients with tuberous sclerosis complex (TSC) with epilepsy: a retrospective cohort study in the UK Clinical Practice Research Datalink (CPRD). BMJ Open. 2017;7(10):e015236.
Słowińska M, Jóźwiak S, Peron A, Borkowska J, Chmielewski D, Sadowski K, et al. Early diagnosis of tuberous sclerosis complex: a race against time. How to make the diagnosis before seizures? Orphanet Journal of Rare Diseases. 2018;13(1):25-.
Stafstrom CE, Carmant L. Seizures and epilepsy: An overview for neuroscientists. Cold Spring Harbor Perspectives in Medicine. 2015;5(6):a022426-a.
Webb DW, Osborne JP. Management of tuberous sclerosis. Irish medical journal. 1991;84(1):7-8.
Winden, K., Bebin, E.M., Jeste, S. et al. Tuberous sclerosis complex. Nat Rev Dis Primers12, 11 (2026). https://doi.org/10.1038/s41572-026-00688-9
Zöllner JP, Franz DN, Hertzberg C, Nabbout R, Rosenow F, Sauter M, et al. A systematic review on the burden of illness in individuals with tuberous sclerosis complex (TSC). Orphanet Journal of Rare Diseases: BioMed Central Ltd.; 2020
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The eyes are affected in over 50% of people with TSC. Vision loss is not common in TSC.
Retinal Hamartomas
There are three types of benign tumours (hamartomas) which can occur on the retina at the back of the eye in TSC: Smooth-surfaced hamartomas, modular or “mulberry” hamartomas and transitional or mixed hamartomas that show characteristics of both of these.
The retinal hamartomas are benign, usually present at birth and rarely change over time. Retinal hamartomas are identified by an ophthalmologist,(a specialist in eyes). Retinal lesions may be difficult to identify without papillary dilation and indirect ophthalmoscopy, particularly difficult to examine in some children who might find it challenging to cooperate. For the most part, treatment of the retinal lesions and repeated ophthalmologic examinations are unnecessary. Normal eye care should be maintained.
While most retinal hamartomas remain dormant, occasionally individuals with TSC have visual impairment resulting from a large hamartoma in the macular region, a 5 mm disc at the back of the eye for detailed vision. Instances of visual loss following retinal detachment (separation of the retina from the outer layer of the eye), vitreous haemorrhage (bleeding), or hamartoma enlargement are rare.
Optic Disc Hamartomas
These are benign hamartomas involving the optic nerve. Although less common than the retinal hamartoma, a defect in the pigment of the iris has also been observed in some individuals with TSC.
Retinal Hypopigmented Lesions
White depigmented patches, reminiscent of the hypopigmented macules on the skin, have also been observed on the retina of some individuals with TSC.
Angiofibroma Near the Eyes
Facial angiofibroma can grow near the eyes or on the eyelids, however this is rare.
Other Causes of Vision Problems
Cortical visual impairment (CVI) is the term used when the brain encounters difficulties in processing information received from the eyes. It can occur in some people with severe seizures or brain tumours.
If a Subependymal giant cell astrocytoma (SEGA) becomes large and blocks the ventricle, vision can be affected and requires urgent medical care. This is a rare occurrence.
For more detailed information, please visit The American Academy of Ophthalmology (https://eyewiki.org/Ophthalmic_Manifestations_of_Tuberous_Sclerosis) and the reference list below.
Last updated on 05/04/2026.
References
The American Academy of Ophthalmology https://eyewiki.org/Ophthalmic_Manifestations_of_Tuberous_Sclerosis Dias PB, Linhares ACB, Hokazono K. Retinal hamartomas at different stages in a patient with tuberous sclerosis: A OCT-SS description. Clin Case Rep. 2023;11(11):e8185.
Hodgson N, Kinori M, Goldbaum MH, Robbins SL. Ophthalmic manifestations of tuberous sclerosis: a review. Clin Exp Ophthalmol. 2017;45(1):81–86. doi: 10.1111/ceo.12806
Mirzayev I, Gunduz AK. Hamartomas of the retina and optic disc. Turkish Journal of Ophthalmology. 2022;52(6):421-31.
Northrup, H. et al. Updated international tuberous sclerosis complex diagnostic criteria and surveillance and management recommendations. Pediatr. Neurol. 123, 50–66 (2021). This reports the latest international consensus recommendations for the diagnosis and management of TSC.
Öhnell, H.M., Kjellström, U., Eklund, E., Pearsson, K., Bekassy, Z. & Gränse, L. (2024)
Ophthalmic manifestations in children with tuberous sclerosis complex. Acta Ophthalmologica, 102, 421–427.
Wan MJ, Chan KL, Jastrzembski BG, Ali A. Neuro-ophthalmological manifestations of tuberous sclerosis: current perspectives. Eye Brain. 2019 Jun 19;11:13-23. doi: 10.2147/EB.S186306. PMID: 31417327; PMCID: PMC6592065.
Winden, K., Bebin, E.M., Jeste, S. et al. Tuberous sclerosis complex. Nat Rev Dis Primers 12, 11 (2026). https://doi.org/10.1038/s41572-026-00688-9
Zipori AB, Tehrani NN, Ali A. Retinal astrocytoma regression in tuberous sclerosis patients treated with everolimus. J AAPOS. 2018;22(1):76–79. doi: 10.1016/j.jaapos.2017.08.009 [DOI]
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Non-cancerous TSC tumours in the heart are called Cardiac rhabdomyomas (cRHM). Cardiac rhabdomyomas are one of the earliest visible growths in patients with TSC and can be visible during prenatal ultrasound scans from about twenty weeks gestation. Cardiac rhabdomyomas are highly associated with TSC, as 75–80% of foetuses with cardiac rhabdomyomas are later diagnosed with TSC, and the presence of multiple tumours suggests an even higher risk of a later TSC diagnosis.
The incidence of cardiac rhabdomyomas varies from 47% to 67%. These can interfere with electrical conduction of the heart, leading to a range of arrhythmias (rhythm abnormalities).
The overall incidence of arrhythmias in patients with TSC with cardiac rhabdomyomas is not known although only a small percentage 5.6% are described as being problematic. Cardiac rhabdomyomas are reported to regress in childhood in up to 96% of cases .
Depending on their location, some individuals may have a more problematic neonatal outcome. Although most cardiac rhabdomyomas of the heart are asymptomatic, for some people symptoms can occur and depend on the number, size and location. Large tumours can obstruct blood flow through the heart causing decreased blood flow to different organs including the lungs. When a cardiac rhabdomyoma is close to the heart’s electrical system, an abnormal rhythm (arrhythmia) can occur, the most common being Wolff Parkinson White (WPW). Large cardiac rhabdomyoma in the heart muscle can cause impaired heart muscle function or cardiomyopathy. A small number of people with cardiac rhabdomyoma may have a heart murmur.
Cardiac evaluation and screening are recommended for all patients with TSC . Rhabdomyomas detected prenatally should be closely monitored throughout the pregnancy via foetal echocardiography, and a baseline echocardiogram and electrocardiogram (ECG) should be obtained in all individuals with TSC after birth or at diagnosis.
Because arrhythmia risks persist after cardiac rhabdomyoma regression, surveillance ECGs are recommended at least every 5 years throughout life.
More frequent or advanced diagnostic assessment may be required for symptomatic patients. Patients who have significant arrhythmias may require treatment with medication or a special cardiac catheterisation procedure.
Last Updated 05/04/2026
References
Bissler JJ, Kingswood CJ. Renal manifestation of tuberous sclerosis complex. American Journal
of Medical Genetics. 2018;178(3):338-47.
Bejiqi R, Retkoceri R, Bejiqi H. Prenatally diagnosis and outcome of fetuses with cardiac
rhabdomyoma - single centre experience. Open Access Macedian Journal of Medical Science.
2017;5(2):193-6.
Hinton, R. B. et al. Cardiovascular manifestations of tuberous sclerosis complex
and summary of the revised diagnostic criteria and surveillance and management
recommendations from the International Tuberous Sclerosis Consensus Group.
J. Am. Heart Assoc. 3, e001493 (2014).
Hurtado-Sierra, D., Ramos Garzon, J. X., Romero-Guevara, S. L., Serrano-Garcia, A. Y.
& Rojas, L. Z. Everolimus and sirolimus in the treatment of cardiac rhabdomyomas in
neonates. Pediatr. Res. https://doi.org/10.1038/s41390-025-04043-8 (2025).
Lazea C, Taranu I, Bolboaca SD. Exploring cardiovascular involvement in tuberous sclerosis:
Insights for pediatric clinicians. Children. 2024;11(6).
Luo C, Ye W-R, Shi W, Yin P, Chen C, He Y-B, et al. Preclinical model systems of ryanodine
receptor 1-related myopathies and malignant hyperthermia: a comprehensive scoping review of
works published 1990–2019. Orphanet Journal of Rare Diseases. 2020;17:106-.
Northrup, H. et al. Updated international tuberous sclerosis complex diagnostic criteria
and surveillance and management recommendations. Pediatr. Neurol. 123, 50–66
(2021). This reports the latest international consensus recommendations for the diagnosis
and management of TSC.
Peng L, Cai Y, Wu J, Ling W, Wu Q, Guo S, et al. Prenatal diagnosis and clinical management of
cardiac rhabdomyoma: a single-center study. Frontiers in Cardiovascular Medicine.
2024;11:1340271.
Tworetzky, W. et al. Association between cardiac tumors and tuberous sclerosis in then fetus
and neonate. Am. J. Cardiol. 92, 487–489 (2003).
Walsh M, Te Water Naude J, Uzun O. Cardiac rhabdomyomas in fetal life and beyond: A single
centre 15-year experience. Archives of Disease in Childhood: Fetal and Neonatal Edition.
2013;98:2.
Winden, K., Bebin, E.M., Jeste, S. et al. Tuberous sclerosis complex. Nat Rev Dis Primers 12, 11
(2026). https://doi.org/10.1038/s41572-026-00688-9
Zhen, L. et al. Prenatal genetic diagnosis of cardiac rhabdomyoma: a single-center
experience. Eur. J. Obstet. Gynecol. Reprod. Biol. 249, 7–10 (2020).
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Lymphangiomyomatosis (LAM) is the most common lung manifestation in TSC and can occur in up to 80% of individuals with TSC. It is more usual to discover LAM in adult females of childbearing age where up to 30% of them can be clinically affected. LAM is usually diagnosed in the second or third decade, however, it is reported that due to insufficient monitoring of the respiratory system, it can go undetected until clinical symptoms appear.
LAM may present in different ways. While some individuals may have deteriorating lung function, repeat pneumothorax and increased morbidity, others may have milder symptoms. LAM is exacerbated by oestrogen and therefore, progestin-only therapy is preferred for birth control or menstrual regulation in women with TSC.
Surveillance for lung manifestations of TSC starts with lung imaging in all women with TSC from ~18 years of age, with repeat imaging every 5 years in asymptomatic women with no radiological findings. If pulmonary involvement is noted, the individual should be monitored closely with annual pulmonary function tests and should have repeated chest scans as needed and according to the international clinical recommendations.
It is important to carry out the recommended computed tomography (CT) scans in order to obtain best outcomes for these individuals. Lung involvement in TSC can be severe, and some individuals will require lung transplantation.
The mTOR inhibitor Sirolimus is frequently used in symptomatic patients. Research is ongoing as to the future treatment of both symptomatic and asymptomatic patients.
Last updated 05/04/2026
References
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).
El-Chemaly, S. et al. Sirolimus and autophagy inhibition in lymphangioleiomyomatosis: results of a phase I clinical trial. Chest 151, 1302–1310 (2017).
Gupta, N. et al. Safety and efficacy of combined resveratrol and sirolimus in lymphangioleiomyomatosis. Chest 163, 1144–1155 (2023).
Johnson J, Somerfield W, Johnson SR. Lymphangioleiomyomatosis in patients with tuberous sclerosis: a national centre audit. Orphanet Journal of Rare Diseases. 2024;19(1):137.
Kingswood JC, d'Augeres GB, Belousova E, Ferreira JC, Carter T, Castellana R, et al. TuberOus SClerosis registry to increase disease Awareness (tosca) - baseline data on 2093 patients.
Orphanet Journal of Rare Diseases. 2017;12(1):2.
Kingswood C, Bolton P, Crawford P, Harland C, Johnson SR, Sampson JR, 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). European Journal of Paediatric Neurology. 2016;20(2):296-308.
O'Mahony AM, Lynn E, Murphy DJ, Fabre A, McCarthy C. Lymphangioleiomyomatosis: a clinical review. Breathe (Sheff). 2020;16(2):200007.
McCarthy C, Gupta N, Johnson SR, Yu JJ, McCormack FX. Lymphangioleiomyomatosis: pathogenesis, clinical features, diagnosis, and management. The Lancet Respiratory Medicine. 2021;9(11):1313-27.
Northrup, H. et al. Updated international tuberous sclerosis complex diagnostic criteria and surveillance and management recommendations. Pediatr. Neurol. 123, 50–66 (2021). This reports the latest international consensus recommendations for the diagnosis and management of TSC.
Winden, K., Bebin, E.M., Jeste, S. et al. Tuberous sclerosis complex. Nat Rev Dis Primers 12, 11 (2026). https://doi.org/10.1038/s41572-026-00688-9
Yu, J. & Henske, E. P. Estrogen-induced activation of mammalian target of rapamycin is mediated via tuberin and the small GTPase Ras homologue enriched in brain. Cancer Res. 66, 9461–9466 (2006).
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Dental enamel pitting (small shallow depressions on the toot surface), dental enamel hypoplasia (decreased enamel thickness), gingival hyperplasia ( swelling or overgrowth of the gums) and intra-oral fibroma ( growths on the tongue, inside the cheeks or palate) are the most common oral manifestations in individuals with TSC. They typically appear between the ages of 4-10 years or puberty. They are a minor diagnostic criteria for TSC.
Dental pitting may cause decay to occur more easily. Regular dental cleanings ad check-ups to catch decay early, usually on a 6-month interval, are important. Your dentist may recommend recalls more frequent than 6 months based on you/your child’s risk for cavities.
Children’s dentists (paediatric dentists) are trained in providing care to children and adults who may need sedation or extra behavioural care. Hospital dentistry is also an option if a patient cannot tolerate the regular office setting.
Last updated on 05/04/2026
References
Mlynarczyk G. Enamel pitting: A common sign of tuberous sclerosis. Annals of the New York Academy of Sciences. 1991;615(1):367-9.
Panwar A, Malik S, Kamarthi N, Gupta S, Goel S, Sharma A, et al. Oral manifestations of tuberous sclerosis complex: A systematic review. Pediatric Dental Journal. 2024;34(3):164-81.
Gosnell ES, Krueger D, Ruck P, Buff-Lindner AH, Horn PS, Griffith M. Oral manifestations and quality of life in children with tuberous sclerosis complex: A descriptive study. Pediatric Dentistry. 2021;43(2):140-4.
Northrup H, Aronow ME, Bebin EM, Bissler J, Darling TN, de Vries PJ, et al. Updated international tuberous sclerosis complex diagnostic criteria and surveillance and management recommendations. Pediatric Neurology. 2021;123:50-66. This reports the latest international consensus recommendations for the diagnosis and management of TSC.
Winden, K., Bebin, E.M., Jeste, S. et al. Tuberous sclerosis complex. Nat Rev Dis Primers 12, 11 (2026). https://doi.org/10.1038/s41572-026-00688-9
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Cysts and tumours similar to those observed in the kidney sometimes appear in other organs. Hepatic (liver) angiomyolipoma AML, and hepatic cysts as well as pancreatic neuroendocrine tumours (PNETs), adrenal angiomyolipoma and thyroid papillary adenoma occur more rarely than other TSC hamartomas.
Hepatic AMLs are reported to occur in 10-25% of individuals with TSC and are more common in adult females. Hepatic AMLs are not associated with the risk of haemorrhage, and hepatic cysts do not usually compromise hepatic function.
Bone lesions are very common in individuals with TSC, but they rarely require intervention. They should not raise concerns about them being cancerous.
Biliary duct hamartomas are said to be problematic in diagnosis as they may be misdiagnosed as cancerous lesions and there is a call for increased research in this field.
Congenital lymphoedema and intestinal lymphangiectasia (PIL) are rare but recognized lymphatic complications in TSC, often stemming from mTOR pathway dysregulation causing lymphatic vessels to malform.
Symptoms are known to usually respond to mTOR inhibitors and is the first line of treatment.
Last updated 05/04/2026
References
Black, M. E. et al. Hepatic manifestations of tuberous sclerosis complex: a genotypic and phenotypic analysis. Clin. Genet. 82, 552–557 (2012).
Boronat, S. & Barber, I. Less common manifestations in TSC. Am. J. Med. Genet. C. Semin. Med Genet 178, 348–354 (2018).
Curatolo P, Specchio N, Aronica E. Advances in the genetics and neuropathology of tuberous sclerosis complex: edging closer to targeted therapy. The Lancet Neurology. 2022;21(9):843-56.
Geffrey, A. L., Shinnick, J. E., Staley, B. A., Boronat, S. & Thiele, E. A. Lymphedema in tuberous sclerosis complex. Am. J. Med. Genet. A 164A, 1438–1442 (2014).
Gomes I, Ribeiro JJ, Palavr F. Monitoring and managing patients with tuberous sclerosis complex: Current state of knowledge. Journal of Multidisciplinary Healthcare. 2022(2022:15):1469-80.
Li, X. P. et al. Tuberous sclerosis complex combined with primary lymphedema: a case report. World J. Clin. Cases 12, 2642–2648 (2024).
Northrup H, Aronow ME, Bebin EM, Bissler J, Darling TN, de Vries PJ, et al. Updated international tuberous sclerosis complex diagnostic criteria and surveillance and management recommendations. Pediatric Neurology. 2021;123:50-66. This reports the latest international consensus recommendations for the diagnosis, surveillance and management in TSC.
Salerno, A. E., Marsenic, O., Meyers, K. E., Kaplan, B. S. & Hellinger, J. C. Vascular involvement in tuberous sclerosis. Pediatr. Nephrol. 25, 1555–1561 (2010).
Sheikh AAE, Nguyen AP, Leyba K, Javed N, Shah S, Deradke A, et al. Biliary duct hamartomas: A systematic review. Cureus. 2022;14(5):e25361.
Winden, K., Bebin, E.M., Jeste, S. et al. Tuberous sclerosis complex. Nat Rev Dis Primers 12, 11 (2026). https://doi.org/10.1038/s41572-026-00688-9
Zhang X, Zhong X, Lin X, Li X, Tian H, Chang B, et al. Tuberous sclerosis complex with multiple organ tumors: Case report and literature review. Frontiers in Oncology. 2022;12:916016.
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The majority of individuals (greater than 80%) with tuberous sclerosis complex (TSC) will develop some form of renal (kidney) disease during their lifetime. These can hold a high risk of morbidity and mortality.
International consensus clinical recommendations for kidney involvement in tuberous sclerosis complex exist. https://pubmed.ncbi.nlm.nih.gov/38443710/
There are three main renal manifestations in TSC: renal cysts, renal angiomyolipoma and renal cell carcinoma.
Renal angiomyolipoma, (AMLs) are usually the greatest concern in TSC and occur in approximately 85% of individuals with TSC. The blood vessels within AMLs are abnormal and can develop weak spots in their wall, called aneurysms, which can burst and lead to life threatening haemorrhage (bleeding). AMLs increase in number and size gradually during the first 10–12 years of life, and more rapidly during adolescence and early adulthood. However, growth continues throughout life. Most of the time both kidneys are involved.
Because AMLs are very vascular in nature, one of the most serious complications associated with AMLs, is that when they bleed, they can cause life-threatening haemorrhage. And AMLs greater than 3 cm are known to carry a remarkably high risk of haemorrhage. Women carry a lifetime risk of haemorrhage of 20% while men run a 10% risk. AMLS can also cause renal insufficiency, arterial hypertension ( High blood pressure) and pain. Historically, the common treatment for AMLs was embolization (procedure to restrict blood flow) and nephrectomy (kidney removal) which frequently resulted in significant disease morbidity. However, with the advent of mTOR inhibitors, consensus guidelines recommended their use as the first line treatment in patients with AMLs ≥ 3cm, even when patients do not have clinical symptoms.
Renal cysts are the second most frequently occurring kidney manifestation of TSC. They are benign fluid filled “holes” in the kidney that occur in about 50% of individuals with TSC and are commonly multiple and bilateral. They occur more commonly in patients with a TSC2 mutation. Individuals with renal cysts have a high risk of reduced renal function and chronic kidney disease even kidney failure, requiring dialysis or transplantation. Renal cysts can lead to hypertension (high blood pressure) but usually do not cause discomfort.
Renal cell carcinoma (cancerous tumours of the kidney). The rate of renal cell carcinoma is not reported to be higher in patients with TSC than the general population, however, it can occur earlier and although rare in TSC, must be kept in mind.
Clinical practice recommendations for kidney involvement in tuberous sclerosis complex: The international consensus clinical recommendations for the surveillance and treatment of renal manifestations in TSC should be adhered to; https://pubmed.ncbi.nlm.nih.gov/38443710/
The kidneys should be scanned, preferably with MRI, at the time of diagnosis, and at 2–3-year intervals if no cysts or angiomyolipoma are identified. If kidney lesions are identified, then the growth of these lesions should be followed using repeated MRI every year or two, unless symptoms develop or the lesion has an unusual growth pattern. Imaging is critical to assess if kidney lesions are present and/or if there has been a change in any of the existing kidney lesions. Individuals with TSC with renal findings should also be screened annually for hypertension, proteinuria and falling GFR228. Standard treatments from other forms of chronic kidney disease also apply to TSC.
[The current methods used to diagnose these renal abnormalities include renal ultrasonography, CT scanning and magnetic resonance imaging (MRI). These are all non-invasive procedures. The renal ultrasound provides the least detailed image of the kidney, while the MRI provides the most detailed. In general, the ultrasound can be sufficient to detect both renal cysts and fat-containing angiomyolipoma but may not provide enough detail to accurately measure and follow the renal lesions and can miss lesions that lack the fat component].There is a paucity of research on the effect of TSC associated kidney disease in pregnancy and more research is required.
Last updated 05/04/2026
References
Bissler JJ, Kingswood CJ. Renal manifestation of tuberous sclerosis complex. American Journal of Medical Genetics. 2018;178(3):338-47.
Courtney M, Mulholland D, O’Neill D, Redmond C, Ryan J, Geoghegan T, et al. Natural growth pattern of sporadic renal angiomyolipoma. Acta Radiologica. 2021;62(2):276-80.
Kingswood JC, Belousova E, Benedik MP, Carter T, Cottin V, Curatolo P, et al. Renal manifestations of tuberous sclerosis complex: Key findings from the final analysis of the tosca study focussing mainly on renal angiomyolipomas. Frontiers in Neurology. 2020;11:972.
Krueger DA, Northrup H, International Tuberous Sclerosis Complex Consensus G. Tuberous sclerosis complex surveillance and management: recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference. Pediatric Neurology. 2013;49(4):255-65.
Mekahli D, Müller R-U, Marlais M, Wlodkowski T, Haeberle S, De Argumedo ML, et al. Clinical practice recommendations for kidney involvement in tuberous sclerosis complex: A consensus statement by the erknet working group for autosomal dominant structural kidney disorders and the era genes & kidney working group. Nature Reviews Nephrology. 2024;20(6):402-20. This reports the latest international consensus recommendations for the kidney management in TSC.
Northrup, H. et al. Updated international tuberous sclerosis complex diagnostic criteria and surveillance and management recommendations. Pediatr. Neurol. 123, 50–66 (2021). This reports the latest international consensus recommendations for the diagnosis and management of TSC.
O'Callaghan FJ, Noakes MJ, Martyn CN, Osborne JP. An epidemiological study of renal pathology in tuberous sclerosis complex. BJU International. 2004;94(6):853-7. Rentz AM, Skalicky AM, Liu Z, Dunn DW, Frost MD, Nakagawa JA, et al. Burden of renal angiomyolipomas associated with tuberous sclerosis complex: Results of a patient and caregiver survey. Journal of Patient-Reported Outcomes. 2018;2:9.
Winden, K., Bebin, E.M., Jeste, S. et al. Tuberous sclerosis complex. Nat Rev Dis Primers 12, 11 (2026). https://doi.org/10.1038/s41572-026-00688-9
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Skin manifestations occur in almost all individuals with TSC and there is a large variety of forms under which they appear. In most cases, the growths themselves are harmless. However manifestations such as those occurring on the face can have negative psychological impacts and effects on the quality of life of individuals and their families . Since the understanding of the role of mTOR inhibitors, various topical treatments have emerged with positive effect. In addition, it has been recorded that those who take oral mTOR inhibitors for other TSC manifestations have seen the regression of their facial angiomyolipoma ( growths on their face) and improved quality of life.
Skin lesions resulting from TSC include:
hypomelanotic macules—patches of skin lighter than the surrounding skin (can be any size or shape or may be the classic “ash-leaf” shape)
Smaller hypomelanotic patches- “confetti macules”
shagreen patch—a patch of skin that is tough and dimpled like an orange peel, often found on the lower back
periungual or subungual fibromas—fibrous growths that appear around the fingernails and toenails
facial angiofibroma—tumours of the face.
fibrous plaques sometimes appear on the forehead of individuals with TSC. There may also be fibrous, hairless scalp plaques surrounded by thin, white tufts of hair.
Hypomelanotic macules are usually the first to be seen in the form of “Ash leaf spots” or smaller “confetti macules” and can be seen more easily when using a Wood’s lamp (an ultraviolet light). These are often visible at birth and a large study of over 2,000 individuals the TOSCA study reported a prevalence of 66%.
Facial Angiomyolipoma usually appear in the first years of life, between 2yrs - 5 yrs of age and they continue to grow throughout the individual’s lifetime. They can be treated with Rapamycin (Sirolimus) cream (an mTOR inhibitor) or by laser.
The periungual and subungual fibromas do not usually occur until much later in life and similar to facial angiofibroma can be treated with mTOR inhibitors.
Individuals with TSC are more susceptible to sunburn and should be careful about sun exposure and use a broad-spectrum sunscreen. These sunscreens protect against UVA and UVB and should have a sun protection factor (SPF) of at least 30. Sunscreen should be applied to all areas exposed to the sun, since tanning of surrounding skin will make the hypomelanotic macules more apparent.
Last updated on 05/04/2026
References
Boggarapu S, Roberds SL, Nakagawa J, Beresford E. Characterization and management of facial angiofibroma related to tuberous sclerosis complex in the United States: retrospective analysis of the natural history database. Orphanet Journal of Rare Diseases. 2022;17(1):355.
Ebrahimi-Fakhari D, Meyer S, Vogt T, Pföhler C, Müller CSL. Dermatological manifestations of tuberous sclerosis complex (tsc). JDDG: Journal der Deutschen Dermatologischen Gesellschaft. 2017;15(7):695-700.
Luo C, Ye W-R, Shi W, Yin P, Chen C, He Y-B, et al. Perfect match: mtor inhibitors and tuberous sclerosis complex. Orphanet Journal of Rare Diseases. 2022;17(1):16.
Northrup, H. et al. Updated international tuberous sclerosis complex diagnostic criteria and surveillance and management recommendations. Pediatr. Neurol. 123, 50–66 (2021). This reports the latest international consensus recommendations for the diagnosis and management of TSC.
Willems LM, Schubert-Bast S, Grau J, Hertzberg C, Kurlemann G, Wiemer-Kruel A, et al. Health-related quality of life in children and adolescents with tuberous sclerosis complex and their caregivers: A multicentre cohort study from Germany. Eur J Paediatr Neurol. 2021;35:111-22.
Winden, K., Bebin, E.M., Jeste, S. et al. Tuberous sclerosis complex. Nat Rev Dis Primers 12, 11 (2026). https://doi.org/10.1038/s41572-026-00688-9
Yang F, Wataya-Kaneda M, Tanaka M, Yang L, Tsuruta D, Katayama I. Topical rapamycin treatment is effective in hypopigmented macules of tuberous sclerosis. Journal of Dermatological Science. 2016;84(1):e28-e9.
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TSC Associated Neuropsychiatric Disorders (TAND).
Apart from the physical manifestations of TSC, most individuals with Tuberous Sclerosis Complex (about 90%) are affected by TSC Associated Neuropsychiatric Disorders (TAND).
These difficulties are categorised under the headings of Behavioural, Psychiatric, Intellectual, Academic, Psychosocial, Neuropsychological levels.
TAND difficulties are shown to be one of the biggest challenges facing individuals with TSC, families, health, social and education professionals.
Please visit the TAND consortium website for comprehensive, up to date information on TAND.
Here’s a two page family-focused introduction to the TAND consensus recommendations.
