Professional Reference articles are written by UK doctors and are based on research evidence, UK and European Guidelines. They are designed for health professionals to use. You may find one of our health articles more useful.
Synonyms: Bourneville's disease; Bourneville-Pringle disease; Pringle's disease; epiloia; tuberous sclerosis complex; tuberose sclerosis
Tuberous sclerosis is a multisystem disorder. It is characterised by the formation of hamartomas in many organs, commonly the brain, skin and kidneys, which account for many of the clinical symptoms. The eyes, heart and lungs are also often involved.
- The incidence at birth is estimated to be 1 in 5,800.
- Tuberous sclerosis is very variable in both the organs involved and severity. Any organ system can be involved, with some more prevalent during infancy and childhood and others more likely to affect adults.
Tuberous sclerosis is caused by mutations in either the TSC1 gene on chromosome 9, or the TSC2 gene on chromosome 16.TSC1 and TSC2 genes encode for hamartin (TSC1) and tuberin (TSC2) form a regulatory complex responsible for limiting the activity of an important intracellular regulator of cell growth and metabolism, known as mammalian target of rapamycin complex 1 (mTORC1).
The mutations may be inherited in an autosomal dominant fashion. Approximately 10-30% of cases of tuberous sclerosis are due to mutations in the TSC1 gene. The frequency of cases due to mutations in the TSC2 gene is higher. TSC2 mutations are associated with more severe disease.
It can present at any age but commonly presents in childhood. It may be detected antenatally in some cases.
It classically presents with skin changes and epilepsy (usually as a result of cortical tubers) before the age of 5 years but the disease can remain latent until adulthood. Some individuals are severely affected, while others have very few features, or may even have subclinical disease because of variable expressivity.
Epilepsy and neurological problems
- Focal seizures and infantile spasms often occur in infancy.It usually occurs secondary to tuber formation in the brain. Complex partial and tonic-clonic seizures can also occur.
- Subependymal giant cell astrocytoma (SEGA) may develop in a minority of patients. These can grow and can lead to hydrocephalus (due to their location at the foramen of Munro). They can present with headache, vomiting, deterioration in seizure control and focal neurological signs.
- Subependymal nodules (SENs) can also occur. They are small lesions found in the lining of the ventricles. They do not enlarge and do not cause hydrocephalus.
Skin and teeth involvement
Most patients have skin changes. Pictures of the lesions are available in 'Further reading & references', below.
All patients should undergo a detailed skin and teeth examamination at time of diagnosis to evaluate for facial angiofibromas, fibrous cephalic plaques, hypomelanotic macules or confetti lesions, ungual fibromas, shagreen patch, defects in tooth enamel, and intraoral fibroma. A skin survey should be performed annually, with focus on rapidly changing or symptomatic lesions:
- Ash leaf macules are areas of depigmentation that may develop during infancy (they may be present at birth). They are usually multiple and are found on the trunk. They can be seen more easily using a Wood's lamp.
- Adenoma sebaceum (facial angiofibromas) are small, reddish nodules that appear on the cheeks and nose, beginning around age four. These lesions eventually enlarge, coalesce, and produce the characteristic adenoma sebaceum appearance.
- Shagreen patches can occur over the sacrum and back (they appear as irregular, thickened skin with orange-peel or leathery texture).
- Forehead plaques are raised, firm, red and usually pigmented skin lesions.
- Ungual fibromas are smooth, firm, flesh-coloured growths adjacent to, or arising from underneath, the nails. Usually characteristic of tuberous sclerosis but a single lesion can occasionally occur due to trauma.
- Poliosis is a localised patch of white hair that can affect the scalp hair or the eyelids.
- Skin tags can occur in the axillae, groins, and around the head and neck.
- Confetti lesions are a cluster of hypomelanotic lesions that have a reticulated appearance. They can develop anywhere on the skin.
NB: café-au-lait spots are not a diagnostic sign.
- Renal angiomyolipoma may be multiple. They are benign hamartomas of the kidney. Usually, they are asymptomatic in childhood. In adults, they can rupture leading to intraperitoneal or intrarenal/ureteric haemorrhage. This can present as haematuria, abdominal pain and hypovolaemia. Obstruction can occur as they enlarge.
- Polycystic kidney disease, single or multiple simple renal cysts, renal calculi and chronic kidney disease may occur.[1, 4]
- Pulmonary lymphangioleiomyomatosis (LAM) most often affects females over 18 years old and presents with shortness of breath.May lead to progressive deterioration in respiratory function with changes similar to emphysema. Pneumothoraces can occur.
- Multifocal micronodular pneumocyte hyperplasia (MMPH) may occur and affects men and women. It appears as multiple nodules on CXR or CT scan. It doesn't usually cause symptoms and tends to be an incidental finding. Management is by observation.
Cognitive and behavioural problems
Tuberous sclerosis is associated with a wide range of cognitive and behavioural problems, including:
- Learning difficulties.
- Social communication deficits.
- Receptive and expressive language deficits.
- Attentional deficits (selective attention, sustained attention and attentional switching).
- Executive deficits (planning, poor sequencing, perseveration).
- Memory deficits (working memory, episodic memory).
- Motor abnormalities (fine motor, gross motor, movement disorders).
- Autism, Asperger’s syndrome and other autism spectrum disorders (ASDs).
- Attention deficit hyperactivity disorder (ADHD) and related disorders.
- Aggression, rage outbursts and temper tantrums.
- Negativity (temporary resistance to change).
- Emotional lability.
- Depressive disorders.
- Anxiety disorders.
- Sleep disorders.
- Epilepsy-related psychotic disorders.
Cardiac rhabdomyomas are seen in the majority of young children with tuberous sclerosis. They may be the first sign of tuberous sclerosis in young children and may be detected antenatally. Most spontaneously regress with no clinical consequence. However, during puberty, they may enlarge or appear de novo. Therefore, this group should be observed for potential clinical signs (heart failure, arrhythmias, heart murmurs) and monitored using echocardiography.
- Hepatic angiomyolipomas can also occur, particularly if there are bilateral renal angiomyolipomas.
- Cyst-like areas can occur within the skeleton, especially the phalanges in the hands and feet. Sclerotic lesions can develop in the pelvis or spine.
- Retinal hamartomas or astrocytomas can also occur but they rarely cause visual symptoms (but do cause an abnormal red reflex).
Diagnosis is usually clinical, based on examination and some of the investigations detailed below. Family history should also be determined. It is based on major and minor features:
- Definite tuberous sclerosis is diagnosed by either two major features or one major feature and two minor features.
- Probable tuberous sclerosis is suggested by one major feature and one minor feature.
- Possible tuberous sclerosis is either one major feature or two minor features.
- Facial angiofibromas or forehead plaque.
- Non-traumatic ungual or periungual fibromas.
- At least three hypomelanotic macules (ash leaf spots).
- Shagreen patch (connective tissue naevus).
- Cortical tuber.
- Subependymal nodule (SEN).
- Subependymal giant cell astrocytoma (SEGA).
- Cardiac rhabdomyoma, single or multiple.
- Lymphangiomyomatosis and/or renal angiomyolipoma.
- Retinal hamartoma.
- Multiple randomly distributed pits in dental enamel.
- Hamartomatous rectal polyps.
- Bone cysts.
- Cerebral white matter radial migration lines.
- Gingival fibromas.
- Non-renal hamartoma.
- Retinal achromic patch.
- Confetti skin lesions.
- Multiple renal cysts.
- Skin tags.
- Positive family history in a first-degree relative.
Investigations will depend on presenting features, but include:
- Fundoscopy, which should be performed to look for retinal lesions.
- Examination of the skin with Wood's ultraviolet (UV) light (shows hypopigmented patches).
- Brain MRI scanning is performed in all patients to look for cortical tubers, SENs and SEGAs. Urgent MRI is needed if SEGA is suspected. Calcified SENs do not tend to be enlarging. Repeat scanning is carried out at intervals.
- Electroencephalography (EEG) is useful when there is epilepsy but not required without it.
- MRI is the preferred imaging modality for renal lesions. Annual assessment of renal function and hypertension.
- ECG is used to detect cardiac arrhythmias. Wolff-Parkinson-White syndrome is the most common arrhythmia in this condition.
- Echocardiography can detect cardiac rhabdomyoma.
- Spirometry, CXR and high-resolution CT scanning are needed if respiratory symptoms are present and pulmonary lymphangioleiomyomatosis is suspected.
- A multidisciplinary approach is required to this multisystem disease.
- Attention to schooling and behavioural disorders will be required along with developmental, psychological and behavioural assessment. A statement of special educational need may be required.
- Guidelines for the assessment of cognitive and behavioural problems in tuberous sclerosis have been drawn up after a consensus workshop in 2003 and are endorsed by the Tuberous Sclerosis Association in the UK and the TS Alliance in the USA.
- The needs of the whole family should be considered.
- Social support, including advice about benefits and disability living allowance, should be available.
- Drugs may be required for specific problems like management of epilepsy. Epilepsy surgery and vagus nerve stimulation may be considered if epilepsy is refractory to medication.
- Some patients with LAM benefit from the use of beta2 agonist inhalers such as salbutamol.
- Chest drain insertion may be needed in a pneumothorax.
- Hormone treatments such as progesterone, buserelin and tamoxifen have been trialled in LAM and may be helpful in some people.
- Antihypertensives may be needed in renal disease.
- Early intervention is indicated for bleeding, symptomatic or potentially disfiguring skin lesions. There is insufficient evidence to guide choice of treatment options between surgical excision, lasers and topical treatments.
- Oral fibromas should be excised surgically if symptomatic or if interfering with oral hygiene. Oral fibromas may recur once excised.
- Surgical excision is needed if a SEGA or a renal cell carcinoma is diagnosed.
- Arterial embolisation or renal sparing surgery may be needed if there is a bleeding renal angiomyolipoma.
- Surgery may also be considered in difficult to control epilepsy.
- Lung transplantation is a possibility in patients with severe LAM.
This should take place at least annually, or more frequently if problems are encountered. Assessment and investigation should look for any problems relating to:
- Neurological problems.
- Cardiac symptoms.
- Skin lesions.
- Renal complications: blood pressure, renal function, haemoglobin, urine dipstick for blood and protein, regular ultrasound imaging.
- Pulmonary complications.
- Developmental and psychological problems.
Because of the wide clinical spectrum, some patients have no decrease in life expectancy or quality of life.
- The most common cause of death is status epilepticus or bronchopneumonia. Renal failure is another common cause.
- Epilepsy can be difficult to control and can contribute to developmental delay. Functional outcome is improved when seizures are controlled at an early age.[9, 10]
- If significant hydrocephalus develops, this can lead to neurological sequelae and blindness.
The prognosis of SEGA is excellent. This should be monitored clinically and radiologically and removed if growing or causing symptoms.
Genetic counselling and screening
Genetic testing and counseling should be offered to patients when they reach reproductive age, and first-degree relatives of affected individuals should be offered clinical assessment and, where a mutation has been identified in the index case, genetic testing.
Trials are looking at drugs that may slow down the growth of the hamartomas responsible for the features of the disease. In theory these drugs will help to regulate cell growth in place of the proteins that are normally produced by the genes TSC1 and TSC2 which are faulty in tuberous sclerosis.[1, 11]Prenatal testing is possible in some cases.
Further reading and references
Krueger DA, Northrup H; Tuberous sclerosis complex surveillance and management: recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference. Pediatr Neurol. 2013 Oct49(4):255-65. doi: 10.1016/j.pediatrneurol.2013.08.002.
Tuberous Sclerosis 1, TSC1; Online Mendelian Inheritance in Man (OMIM)
Northrup H, Krueger DA; Tuberous sclerosis complex diagnostic criteria update: recommendations of the 2012 Iinternational Tuberous Sclerosis Complex Consensus Conference. Pediatr Neurol. 2013 Oct49(4):243-54. doi: 10.1016/j.pediatrneurol.2013.08.001.
Dixon BP, Hulbert JC, Bissler JJ; Tuberous sclerosis complex renal disease. Nephron Exp Nephrol. 2011118(1):e15-20. doi: 10.1159/000320891. Epub 2010 Nov 11.
Guidelines for the assessment of cognitive and behavioural issues in TSC; Tuberous Sclerosis Association
Jozwiak S, Kotulska K, Kasprzyk-Obara J, et al; Clinical and genotype studies of cardiac tumors in 154 patients with tuberous sclerosis complex. Pediatrics. 2006 Oct118(4):e1146-51. Epub 2006 Aug 28.
Fricke BL, Donnelly LF, Casper KA, et al; Frequency and imaging appearance of hepatic angiomyolipomas in pediatric and adult patients with tuberous sclerosis. AJR Am J Roentgenol. 2004 Apr182(4):1027-30.
Curatolo P, Bombardieri R, Jozwiak S; Tuberous sclerosis. Lancet. 2008 Aug 23372(9639):657-68.
Weiner HL, Carlson C, Ridgway EB, et al; Epilepsy surgery in young children with tuberous sclerosis: results of a novel approach. Pediatrics. 2006 May117(5):1494-502.
Jansen FE, Vincken KL, Algra A, et al; Cognitive impairment in tuberous sclerosis complex is a multifactorial condition. Neurology. 2008 Mar 1870(12):916-23. Epub 2007 Nov 21.
Sahin M; Targeted treatment trials for tuberous sclerosis and autism: no longer a dream. Curr Opin Neurobiol. 2012 Oct22(5):895-901. doi: 10.1016/j.conb.2012.04.008. Epub 2012 May 4.
Gusman M, Servaes S, Feygin T, et al; Multimodal imaging in the prenatal diagnosis of tuberous sclerosis complex. Case Rep Pediatr. 20122012:925646. doi: 10.1155/2012/925646. Epub 2012 Oct 2.
I am Pregnant. Doctor have suggested to do exercise but I feel very restless and dull. sometimes I am out of energy it might be because of I am weak. What shall I do?please help me.diskha67586
Disclaimer: This article is for information only and should not be used for the diagnosis or treatment of medical conditions. Patient Platform Limited has used all reasonable care in compiling the information but make no warranty as to its accuracy. Consult a doctor or other health care professional for diagnosis and treatment of medical conditions. For details see our conditions.