Tuberous sclerosis

Author: Vanessa Ngan, Staff Writer, 2003.


What is tuberous sclerosis?

Tuberous sclerosis or tuberous sclerosis complex (TSC) is a genetic disorder that is characterised by hamartomas in many organs, but particularly the skin, brain, eye, kidney and heart. Hamartomas are non-cancerous malformations composed of overgrowth of the cells and tissues that normally occur in the affected area and include naevi (birthmarks). Tuberous sclerosis is also known as epiloia.

Skin lesions, epileptic seizures and developmental delay/behavioural problems are the main features of tuberous sclerosis complex. However, individuals with the condition may be affected in many different ways and with differing degrees of severity. Some patients may have very few or no symptoms at all, whilst others may be severely affected with a multitude of symptoms.

What causes tuberous sclerosis and who gets it?

Tuberous sclerosis is a genetic disorder due to mutation in one of two genes:

  • TSC1, which produces a protein called hamartin (10–30% of cases)
  • TSC2, which produces a protein called tuberin

About one third of all cases of tuberous sclerosis are inherited from an affected parent. All other cases are due to sporadic new mutations occurring in the early stages of life, most often mutations of TSC2.

People of all races and sex may be affected. The condition may become apparent any time from infancy to adulthood but usually occurs between 2-6 years of age.

Genetics of Tuberous sclerosis*

*Image courtesy Genetics 4 Medics

What are the skin signs of tuberous sclerosis complex?

Skin lesions are found in 60-70% of cases of tuberous sclerosis.

LesionFeatures
Angiofibromas
  • Facial rash that appears as a spread of small pink or red spots across the cheeks and nose in a butterfly distribution
  • Usually appear between 3-10 years of age and increase in size and number until adolescence
  • Also found around the nails, scalp and forehead
  • Previously incorrectly called adenoma sebaceum
Angiofibromas
Ungual fibromas
  • Smooth, firm, flesh-coloured lumps that emerge from the nail folds
  • Periungual sites (around the nail) are more common than subungual sites (under the nail)
  • More common on feet than hands
  • Longitudinal groove in the nail may occur without visible fibroma
  • Short red (splinter haemorrhages) or white streaks (leukonychia) may be seen on affected nails
Periungual fibromas
Shagreen patch
  • Flesh coloured orange-peel connective tissue naevi of varying sizes, usually on the lower back
Shagreen patches
Ovoid or ash leaf-shaped white macules
  • May be present at birth or early infancy
  • 3 or more white spots at birth suggests diagnosis of tuberous sclerosis
Ash leaf marks

See more images of tuberous sclerosis ...

Other organ involvement

Epilepsy is present in about 70% of patients with tuberous sclerosis.

  • Usually begins in infancy or early childhood and may precede appearance of skin lesions by years
  • The greater the number of tumours (cortical tubers) in the brain, the greater the severity of seizures.

Developmental delay and behavioural problems may also occur. Symptoms include mild to severe mental retardation, autism, attention deficit disorder (ADD), anxiety, depression, paranoia and schizophrenia.

Other signs and symptoms of tuberous sclerosis include:

  • Eye involvement: white spots on the iris and white lumps on the retina
  • Heart, gastrointestinal and kidney tumours
  • Lung changes

What treatment is available?

Tuberous sclerosis is a multisystem disorder so treatment from a team of specialist doctors is usually necessary.

Skin lesions, particularly facial angiofibromas, may be psychologically distressing for some patients. Laser treatment or electrosurgery can be used to remove angiofibromas.

The topical mTOR inhibitor sirolimus 0.2% gel (also called rapamycin) has proved helpful in reducing angiofibromas in a clinical trial involving 36 adults and children. One study has also reported improvement in hypopigmented macules. A larger prospective, multicentre, randomised, double-blind, vehicle-controlled trial enrolled 179 patients with tuberous sclerosis-related facial angiofibromas and found improvement in more than 80% of patients treated with topical 1% rapamycin with most improvement occurring in the first month. It was well tolerated [5–8].

 

Related Information

References

  1. OMIM – Online Mendelian Inheritance in Man (search term Tuberous sclerosis)
  2. Book: Textbook of Dermatology. Ed Rook A, Wilkinson DS, Ebling FJB, Champion RH, Burton JL. Fourth edition. Blackwell Scientific Publications.
  3. Tuberous Sclerosis Complex – GeneTests GeneReviews
  4. Schwartz RA, Fernandez G, Kotulska K, Jozwiak S. Tuberous sclerosis complex: Advances in diagnosis, genetics, and management. J Am Acad Dermatol 2007;57:189-202. Medline
  5. Foster RS, Bint LJ, Halbert AR. Topical 0.1% rapamycin for angiofibromas in paediatric patients with tuberous sclerosis: A pilot study of four patients. Australas J Dermatol. 2012 Feb;53(1):52-6. doi: 10.1111/j.1440-0960.2011.00837.x. Epub 2011 Dec 29.
  6. Wataya-Kaneda M, Tanaka M, Yang L, et al. Clinical and Histologic Analysis of the Efficacy of Topical Rapamycin Therapy Against Hypomelanotic Macules in Tuberous Sclerosis Complex. JAMA Dermatol. 2015;151(7):722-730.
  7. Wataya-Kaneda M, Nakamura A, Tanaka M, Hayashi M, Matsumoto S, Yamamoto K, Katayama I. Efficacy and Safety of Topical Sirolimus Therapy for Facial Angiofibromas in the Tuberous Sclerosis Complex A Randomized Clinical Trial. JAMA Dermatol. Published online November 12, 2016. doi:10.1001/jamadermatol.2016.3545
  8. Koenig MK, Bell CS, Hebert AA, et al. Efficacy and Safety of Topical Rapamycin in Patients With Facial Angiofibromas Secondary to Tuberous Sclerosis ComplexThe TREATMENT Randomized Clinical Trial. JAMA Dermatol. Published online May 23, 2018. doi:10.1001/jamadermatol.2018.0464. Journal.

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