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Key points
- Tuberous sclerosis: autosomal dominant neurocutaneous disorder; incidence ~1 in 6000–10,000; usually presents in infancy/childhood.
- Aetiology: pathogenic variants in TSC1 (hamartin) or TSC2 (tuberin); overactivation of mTOR pathway → benign tumours (hamartomas); TSC2 = more severe disease.
- Clinical features: seizures, ADHD, ash-leaf macules, facial angiofibromas, shagreen patches, angiomyolipomas, LAM, retinal hamartomas, cardiac rhabdomyomas.
- Differentials: hypomelanotic lesions (vitiligo), angiofibromas (acne), LAM (asthma/COPD), rhabdomyomas (isolated cardiac tumours).
- Investigations: MRI brain (tubers, SEGA), ECG, fundoscopy, U&Es, MRI abdomen, HRCT chest, EEG; genetic testing for TSC1/TSC2 variants.
- Diagnosis: 2021 criteria – definite TSC = 2 major or 1 major + 2 minor features; or pathogenic TSC1/TSC2 variant.
- Management: life-long surveillance; vigabatrin for infantile spasms, mTOR inhibitors (e.g. sirolimus) for LAM/SEGAs, surgery/embolisation for renal tumours, laser/dermabrasion for facial lesions.
- Monitoring: annual skin, dental, ophthalmic review; periodic MRI brain/abdomen, HRCT chest, ECG, echo depending on organ involvement.
- Complications: ESRD (esp. TSC2), renal cell carcinoma (4%), LAM; mTOR inhibitors cause stomatitis, infections, menstrual issues.
- Prognosis: highly variable; mortality often due to seizures or renal complications.
Introduction
Tuberous sclerosis complex (TSC) is an autosomal dominant neurocutaneous disorder characterised by variable benign tumours in multiple organ systems. It is a progressive condition and may present at any age, although it is usually diagnosed in infancy or childhood.1
TSC affects approximately 1 in 6000 – 1 in 10,000 live births. The incidence does not differ by sex or ethnicity.1
Aetiology
A genetic variant in TSC1 on chromosome 9, which encodes hamartin, or TSC2 on chromosome 16, which encodes tuberin, is responsible for the manifestation of the clinical features of TSC. These two proteins are involved in cell division and proliferation.
Pathological genetic variation in these genes leads to dysfunctional protein products and overactivation of the mechanistic target of the rapamycin (mTOR) pathway.2 This leads to the development of benign tumours (hamartomas) in multiple organs.3
Genetic variants in TSC2 account for most cases, whilst only one-third of cases result from a pathogenic variant in TSC1. Pathogenic variants in TSC2 are associated with a more severe disease course.3
Clinical features
Clinical features of TSC are categorised according to the affected organ through which they manifest. This can be through a variety of mechanisms, including mass effect or aberrant organ function.
Neurological
Dermatological
- Hypomelanotic macules (ash leaf macules)
- Facial angiofibromas (adenoma sebaceum)
- Shagreen patches
- Ungual fibromas
- Intraoral fibromas5
Teeth
- Dental enamel pits6
Cardiac
- Ventricular outflow tract obstruction and cardiac arrhythmias7
Renal
- Angiomyolipomas8
Pulmonary
- Lymphangioleiomyomatosis (LAM)9
Ophthalmic
- Retinal hamartomas
- Angiofibromas of the eyelid
- Refractive errors10
Differential diagnoses
Many of the features of TSC are non-specific and may occur in isolation or as part of another condition and are thus not pathognomonic for TSC.
Skin lesions
- Hypomelanotic lesions: can occur in isolation in otherwise healthy individuals. They may also be seen in association with dermatological conditions such as vitiligo, piebaldism and Vogt-Koyanagi-Harada syndrome.
- Ungual fibromas: can also be caused by trauma
- Angiofibromas: can be difficult to discern from acne vulgaris, acne rosacea or multiple trichoepithelioma. They may also present as non-endocrine tumours in multiple endocrine neoplasia type 1 (MEN1).
Cardiac
- Cardiac rhabdomyoma: may occur in isolation in healthy individuals
Renal
- Angiomyolipoma: initially may be confused with renal cell carcinoma, oncocytoma or metastatic lesions
Pulmonary
- Lymphangioleiomyomatosis: may be difficult to distinguish from asthma, pulmonary hypertension or emphysema. It is notoriously difficult to diagnose, but is more common in females and is oestrogen-sensitive.3
Investigations
Bedside investigations
Relevant bedside investigations include:
- Basic observations: to assess for hypertension
- ECG: to assess for underlying conduction defects
- Eye exam with dilated fundoscopy: to assess for retinal findings (astrocytic hamartoma and achromic patch) and visual field deficits
Laboratory investigations
Relevant laboratory investigations include:
- Urea and electrolytes: to evaluate renal function
Imaging
Relevant imaging includes:
- MRI brain: to assess for subependymal nodules, tubers, migration defects and subependymal giant cell astrocytoma (SEGA)
- Echocardiogram: to assess for cardiac rhabdomyoma
- MRI abdomen: to assess for the presence of renal cysts and angiomyolipomas
- High-resolution CT scan (HRCT): to assess for the presence of lung cysts in asymptomatic females and symptomatic males at 18 years or older
Specialised tests
In specific circumstances, specialised tests may be indicated, which can include:
- EEG: to assess for seizure activity. Hypsarrhythmia is suggestive of infantile spasm.
- Lung function tests and 6-minute walk test: performed in patients with evidence of cystic lung disease consistent with LAM on CT thorax
- Panoramic radiograph of teeth: performed in all patients 7 years or older due to the risk of jaw bone cyst formation11
Diagnosis
TSC is diagnosed based on clinical criteria or genetic criteria. Diagnostic criteria were updated in 2021 by the International Tuberous Sclerosis Complex Consensus Group.1
Clinical criteria
Definite TSC is diagnosed if:
- Two major criteria, or
- One major and two or more minor criteria are present
Possible TSC is diagnosed if:
- One major or
- Two or more minor features are present
Table 1. The major and minor diagnostic criteria of TSC 1, 3, 7, 11
| Major criteria | Minor criteria |
|
|
*A combination of LAM and angiomyolipomas without other features does not meet the criteria for a definite diagnosis.
Genetic criteria
Identification of a known pathogenic or likely pathogenic genetic variant in TSC1 or TSC2 is sufficient for diagnosing TSC.
As genomic testing becomes more widespread, it is important to note that not all genetic variants identified in TSC1 or TSC2 will cause TSC, and only validated variants that have been well-established to cause disease should be interpreted as pathogenic. Other variants (including variants of uncertain significance) need to be interpreted cautiously in collaboration with a medical geneticist or dedicated specialist.1, 3
Management
Management of TSC is directed at life-long surveillance to monitor for common manifestations and their associated complications, which are then addressed accordingly.
Skin lesions
Monitoring
All patients require a skin examination at diagnosis and then yearly thereafter.11
Management
Sun protection is necessary because hypomelanotic lesions are susceptible to sunburn, and ultraviolet-induced DNA damage may contribute to the development of facial angiofibromas.12 Facial angiofibromas may have cosmetic implications for many patients, and laser therapy and dermabrasion may be used to treat these.13
Ophthalmic lesions
Monitoring
All patients require a complete ophthalmologic examination, including dilated fundoscopy at the time of diagnosis and then annually to assess for visual field defects and retinal abnormalities.11
Management
The lesions do not require specific treatment. Refractive errors are corrected with eyeglasses.10
Cardiac disease
Monitoring
Asymptomatic patients should have an ECG every 3-5 years. Those with a rhabdomyoma require a follow-up echocardiogram every 1-3 years until regression of the rhabdomyoma. Symptomatic patients require more frequent monitoring.11
Management
Most cardiac rhabdomyomas regress spontaneously, however, some may cause arrhythmias or outflow tract obstruction. Those patients with symptoms will require surgical resection.7
Renal disease
Monitoring
MRI of the abdomen should be repeated every 1-3 years because of the potential for renal cysts development.11
Management
The decision to treat depends on the risk of malignant transformation and the risk of bleeding. Treatment options include single artery embolisation or surgical resection.14
Pulmonary disease
Monitoring
For females who remain asymptomatic, an HRCT should be repeated every 5 years. Repeat HRCT should be performed every 1-3 years for patients with cystic disease. These patients also require annual lung function tests and a 6-minute walk test.11
Management
The management of LAM depends on the degree of lung function impairment. Patients with mild lung function impairment undergo monitored observation with interval clinical assessment and pulmonary function testing.
Those with moderate to severe lung function impairment are treated with mTOR inhibitors, of which sirolimus is first-line.11
Dental lesions
Monitoring
All patients require a dental examination at diagnosis and then 6-monthly thereafter. This is to evaluate for enamel pits and intra-oral fibromas.11
Management
Oral fibromas can be surgically removed if they are symptomatic or interfering with oral hygiene. Enamel pits may be treated with sealants if oral hygiene is affected.6, 11
Seizures
Management
Infantile spasms are commonly associated with TSC and are responsive to vigabatrin. Focal seizures are treated with anti-epileptics in the same way as the general population.2, 4, 11
Brain tumours
Monitoring
In asymptomatic patients who are under 25 years, an MRI brain is required every 1-3 years to monitor for SEGA. More frequent monitoring is required in patients with large or growing SEGAs or SEGAs causing ventricular dilatation.11
Management
Targeted treatment for brain tumours, such as SEGAs, includes laser ablation, surgery and mTOR inhibitors (e.g. everolimus).15
Neuropsychiatric disorders
Those with TSC have a higher risk of developing neuropsychiatric disorders such as attention deficit hyperactivity disorder (ADHD), autism spectrum disorder and intellectual disability. Patients should be screened for these conditions at the time of diagnosis and annually thereafter. Management is directed at the specific disorder.16
Complications
End-stage renal disease secondary to renal angiomyolipomas (AML) and cysts is more common in TSC2 than in TSC1. Whilst less common, 4% of patients will develop renal cell carcinoma. The prevalence of renal complications increases with age. AML is universally present in patients who have LAM.8
mTOR inhibitors are associated with stomatitis, menstrual irregularities and increased susceptibility to infection.1
Prognosis
The prognosis for TSC is variable, considering the wide range of manifestations associated with the condition. Mortality is caused mainly by complications, including seizures or renal angiomyolipomas.1
Reviewer
Dr Russel Tilney
Clinical Research Fellow at UCL Institute of Neurology
Editor
Dr Jamie Scriven
References
- Rout P, Zamora EA, Aeddula NR. Tuberous sclerosis. StatPearls. 2024. Available from: [LINK].
- 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. Available from: [LINK].
- Northrup H, Koenig MK, Pearson DA, et al. Tuberous Sclerosis Complex. GeneReviews®. 1999. Available from: [LINK].
- Yates JRW, MacLean C, Higgins JNP, et al. The Tuberous Sclerosis 2000 Study: presentation, initial assessments and implications for diagnosis and management. Archives of Disease in Childhood. 2011. Available from: [LINK].
- Webb DW, Clarke A, Fryer A, et al. The cutaneous features of tuberous sclerosis: a population study. British Journal of Dermatology. 1996. Available from: [LINK].
- Ammari MM, Ribeiro de Souza IP, Maia LC, et al. Oral findings in a family with tuberous sclerosis complex. Special Care in Dentistry. 2014. Available from: [LINK].
- Hinton RB, Prakash A, Romp RL, 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. Journal of American Heart Association. 2014. Available from: [LINK].
- Rakowski SK, Winterkorn EB, Paul E, et al. Renal manifestations of tuberous sclerosis complex: incidence, prognosis, and predictive factors. Kidney International. 2006. Available from: [LINK].
- Kristof AS, Zhi Li P, Major P, et al. Lymphangioleiomyomatosis and Tuberous Sclerosis Complex in Quebec. Chest Journal. 2015. Available from: [LINK].
- Hodgson N, Kinori M, Goldbaum MH, et al. Ophthalmic manifestations of tuberous sclerosis: a review. Clinical and Experimental Ophthalmology. 2016. Available from: [LINK].
- Northrup H, Aronow ME, Bebin EM, et al. Updated International Tuberous Sclerosis Complex Diagnostic Criteria and Surveillance and Management Recommendations. Pediatric Neurology. 2021. Available from: [LINK].
- Riikonen R, Simell O. Tuberous sclerosis and infantile spasms. Developmental Medicine and Child Neurology. 1990. Available from: [LINK].
- Amin S, Kingswood JC, Bolton PF, et al. The UK guidelines for management and surveillance of Tuberous Sclerosis Complex. QJM: An International Journal of Medicine. 2018. Available from: [LINK].
- Fohlen M, Ferrand-Sorbets S, Delalande O, et al. Surgery for subependymal giant cell astrocytomas in children with tuberous sclerosis complex. Child’s Nervous System. 2018. Available from: [LINK].
- Curatolo P, Moavero R, de Vries PJ. Neurological and neuropsychiatric aspects of tuberous sclerosis complex. The Lancet Neurology. 2015. Available from: [LINK].
Image references
- Figure 1-4. DermNet. Tuberous sclerosis. License: [CC BY-NC-ND 3.0 NZ].
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