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Tuberous sclerosis

Adenoma sebaceum; Bourneville disease; Bourneville Pringle Syndrome; Epiloia; Phakomatosis TS; Tuberous Sclerosis Complex; Tuberous Sclerosis-1

Tuberous sclerosis (TSC) is a rare, multi-system disorder, inherited as an autosomal dominant and characterized by epilepsy, mental disability, and small non-malignant tumours on the skin and other body tissues.

Hamartomas form in many organs like skin, brain, eye, kidney and heart.

Epidemiology
Prevalence Different sources estimate prevalence from 1 in 6,000 to 1 in 50,000. The severity varies considerably and there are formes frustes. This may account for the difference in estimated prevalence. Sometimes it is diagnosed for the first time in adults.
The Tuberous Sclerosis Organisation of the UK estimates a prevalence of 1 in 7,000 with 8,000 affected individuals in the UK.

Risk Factors It is caused by mutations of the TSC1 and TSC2 tumour suppressing genes.
TSC1 makes a protein called hamartin, and TSC2 produces a protein called tuberin. Together they regulate cell growth¹ and prevent the overgrowth of cells into tumours. When a gene is mutated, either hamartin or tuberin is ineffective, leading to the formation of benign tumours or hamartomas.

Some sources claim that about ? of the mutations are inherited from a parent who has the condition and ? arise as mutations usually involving the TSC2 gene. Other sources claim that 70% have a family history. The difference is probably due to investigating the parents where it is not readily apparent.

Presentation
Clinical features Tuberous sclerosis typically presents shortly after birth. The characteristic features are:

• Epilepsy affects 70% and often starts with "salaam fits" in infancy.
• Mental retardation in 50 to 60%, being severe in 25%.
• Distinctive skin lesions and benign tumour-like nodules that are hamartomas of the brain, retina, heart, kidneys, lungs and other organs.
• Cyst-like areas within the skeleton, especially the phalanges.
• Skin lesions include areas of depigmentation that may develop during infancy and small, reddish nodules that may appear on the cheeks and nose beginning around age four. These lesions eventually enlarge, coalesce, and produce the characteristic sebaceous adenomas.
  

The classic triad of adenoma sebaceum, epilepsy and mental retardation is seen in older children but not in young ones presenting with fits, as the rash does not develop fully until the sebaceous glands hypertrophy at puberty. It may consist of telangiectasiae over the nose or elevated reddish-yellow lesion over the cheeks and bridge of the nose, consisting of small tumours of sebaceous glands with hyperkeratosis.

Other skin lesions include the Moroccan leather shagreen patches over the sacrum and back, ichthyosis, café au lait spots, subungual fibromas, telangiectasiae and vitiligo.

Diagnosis² is based on major and minor features:

• Definite tuberous sclerosis is diagnosed by either 2 major features or 1 major feature and 2 minor features.
• Probable tuberous sclerosis is suggested by 1 major feature and 1 minor feature.
• Possible tuberous sclerosis is either 1 major feature or 2 or more minor features.

Major features

• Facial angiofibromas or forehead plaque
• Nontraumatic ungual or periungual fibromas
• At least 3 hypomelanotic macules
• Shagreen patch (connective tissue naevus)
• Multiple retinal nodular hamartomas
• Cortical tuber
• Subependymal nodule
• Subependymal giant cell astrocytoma
• Cardiac rhabdomyoma, single or multiple
• Lymphangiomyomatosis
• Renal angiomyolipoma

Minor features

• Multiple randomly distributed pits in dental enamel
• Hamartomatous rectal polyps
• Bone cysts
• Cerebral white matter radial migration lines
• Gingival fibromas
• Nonrenal hamartoma
• Retinal achromic patch
• Confetti skin lesions
• Multiple renal cysts

Differential Diagnosis

• In early life it may present simply as epilepsy or as learning difficulties.
• Angiofibromas differentiate from acne vulgaris by telangiectasia, absence of comedones and pustules, and relatively asymptomatic nature.
• Shagreen patch (must be differentiated from connective tissue naevi).
• Hypopigmented spots may need to be differentiated from naevus anaemicus, naevus achromicus, and early vitiligo.

Investigations

• CT or MRI is performed in all patients.
• EEG is useful when there is epilepsy but not required without it.
• Renal ultrasound as renal tumours are common.
• ECG is to detect cardiac arrhythmias. Wolff-Parkinson-White syndrome is the commonest arrhythmia in this condition.
• Echocardiography is to detect cardiac rhabdomyoma. Most occur in neonates and the lesions disappear as the child grows older.
• Neurodevelopmental screening for behavioural and developmental disorder and reassess periodically. Newly diagnosed adults with normal social and cognitive function do not require formal testing.
• DNA testing is not yet available.
• Repeat CT scanning every 1 to 3 years where the diagnosis is suspected but not confirmed.
• Neurodevelopmental testing should assess learning difficulties, which are common, and other features like autism and attention deficit. Repeat the assessment around school entry and then reassess periodically if there are educational and behavioural concerns.
• Renal ultrasound is recommended every 1 to 3 years. Large lesions and any that have grown substantially should be examined more often.
• Pulmonary function testing is not needed routinely. Women should undergo chest CT scanning at least once on reaching adulthood.

Associated Diseases About 50% have some type of mental problem like hyperactivity, autism, or aggression. Autism is present in about 25% with autistic spectrum, usually Asperger's syndrome, in another 25%.

Family members

• If only one child affected, evaluation of parents is more important than siblings or relatives.
• CT of the head is a good screening tool but MRI often detects lesions that are not specific.
• Renal ultrasound is important as renal lesions occur in about 80% of patients.
• Echocardiography is not required in adults as cardiac rhabdomyomas usually disappear by adulthood.
• Molecular diagnosis is not yet commercially available but it may be soon³.

Management
Non-Drug A multidisciplinary approach is required to this multi-system disease. Attention to schooling and behavioural disorders will be required along with developmental assessment.

Drugs Drugs may be required for specific problems like management of epilepsy.

Surgical Facial angiofibromas respond to laser treatment. Either laser or diathermy can remove ungual fibromas.

Complications If there is a marked deterioration in mental function consider uncontrolled epilepsy. Convulsions may not be obvious. They can also cause sleep disturbances.

Prognosis Tuberous sclerosis shows a wide spectrum. Some individuals are severely affected, while others have very few features. Forme frustes are common. About a ¼ of severely affected infants die before age 10, and 75% die before age 25 year. The prognosis for the individual diagnosed late in life with few cutaneous signs depends upon internal tumours.

Prevention Genetic counselling can be given but not ante-natal screening.

References Used

1. van Slegtenhorst M, Nellist M, Nagelkerken B, et al; Interaction between hamartin and tuberin, the TSC1 and TSC2 gene products.;Hum Mol Genet 1998 Jun;7(6):1053-7.[abstract]
2. Roach ES, Gomez MR, Northrup H; Tuberous sclerosis complex consensus conference: revised clinical diagnostic criteria.;J Child Neurol 1998 Dec;13(12):624-8.[abstract]
3. Kwiatkowski DJ, Short MP; Tuberous sclerosis.;Arch Dermatol 1994 Mar;130(3):348-54.[abstract]

Internet and Further Reading

• Nambi R. on eMedicine
• Forfar & Arneil's Textbook of Pediatrics, 6th edition. eds McIntosh, Helms, Smythe. Churchill Livingstone 2003. Standard textbook of paediatrics with some different opinions from e-medicine
• [www.tuberous-sclerosis.org] Patient support group in UK

Acknowledgements EMIS is grateful to the Mentor authoring team for writing this article. The final copy has passed peer review of the independent Mentor GP authoring team. ©EMIS 2004.

Last issued 30 Aug 2006