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Conditions

Tuberous sclerosis complex

Tuberous sclerosis complex is a rare genetic condition that is characterised by benign tumours in the skin, bones and some organs. It is often associated with seizures and neurodevelopmental conditions.

Overview

Tuberous sclerosis complex (TSC) is a rare, highly variable genetic condition characterised by the growth of benign tumours in the skin, brain, heart, kidneys, lungs and bones. It is often associated with seizures and neurodevelopmental conditions. It is caused by constitutional pathogenic variants in either of the tumour suppressor genes: TSC1 or TSC2.

Clinical features

TSC presents with different features at different ages.

Prenatal

  • Cardiac symptoms:
    • antenatal scans can identify rhabdomyomas, which typically regress in late pregnancy or early infancy (if multiple rhabdomyomas are identified, the likelihood of the diagnosis being TSC approaches 100%; if only one is identified, the chance that TSC is the cause falls to around 50%).
  • Neurological symptoms:
    • focal cortical dysplasias (cortical tubers) may be identified on fetal brain imaging after 20 weeks of pregnancy.

Infancy

  • Skin features:
    • hypomelanotic macules (sometimes called ash leaf macules); and
    • confetti skin lesions.
  • Neurological symptoms:
    • focal cortical dysplasias (cortical tubers);
    • subependymal nodules; and
    • infantile spasms.

Childhood

  • Skin features:
    • the following features begin to develop in childhood, and become more prevalent with age:
      • angiofibromas (typically over the cheeks and nose);
      • fibrous cephalic plaques (typically of the forehead);
      • ungal fibromas; and
      • shagreen patches.
  • Renal symptoms:
    • angiomyolipomas (50%–60% of cases; increase in prevalence with age); and
    • cysts (if early onset renal cystic disease is present along with other features, consider a contiguous gene deletion involving TSC2 and ADPKD1).
  • Neurological symptoms:
    • subependymal giant cell astrocytomas (can cause hydrocephalus);
    • epilepsy (present in 80% of patients with a variety of seizure types; some are refractory to treatment);
    • developmental delay and intellectual disability (more common in those with epilepsy; less than 50% of patients have a normal IQ); and
    • tuberous sclerosis-associated neuropsychiatric disorder (TAND), which includes:
  • Musculoskeletal symptoms:
    • sclerotic bone lesions (usually detected incidentally on imaging).
  • Dental features:
    • dental enamel pits.

Adolescence and adulthood

  • Neurological symptoms:
    • TAND:
      • hyperactivity and impulsivity;
      • aggression and self-harm;
      • anxiety;
      • depression; and
      • sleep conditions.
  • Respiratory symptoms:
    • lymphangioleiomyomatosis (LAM) – this is reported almost exclusively in adult females; and
    • multifocal micronodular pneumocyte hyperplasia – this is a benign lung lesion requiring no follow up (reported in both sexes, less common than LAM and typically seen at a younger age).
  • Renal symptoms:
    • renal cell carcinoma (2%–4% of cases; increases in prevalence with age).

Diagnosis

Diagnosis of TSC can be clinical or genetic. Updated international tuberous sclerosis complex diagnostic criteria suggest that a definite clinical diagnosis of TSC can be made in a patient with two major features of the condition, or one major feature together with two minor features. One major feature, or two or more minor features, suggests a possible clinical diagnosis of TSC.

The major features of TSC are:

  • hypomelanotic macules (at least three that are at least five millimetres in diameter) – these are also known as ash leaf spots; a Woods light may help to visualise them;
  • angiofibromas (at least three) or fibrous cephalic plaque;
  • ungual fibromas (at least two);
  • shagreen patch;
  • multiple retinal hamartomas;
  • cortical dysplasias, such as multiple cortical tubers and/or cerebral white matter radial migration lines;
  • subependymal nodules (at least two);
  • subependymal giant cell astrocytoma;
  • cardiac rhabdomyoma;
  • LAM; and
  • angiomyolipomas (AML – at least two).

Note that, because LAM and AML may arise as isolated findings without systemic features, they cannot be used in isolation in making a clinical diagnosis of TSC.

The minor features of TSC are:

  • confetti skin lesions;
  • dental enamel pits (more than three);
  • intraoral fibromas (at least two);
  • retinal achromic patch;
  • multiple renal cysts;
  • non-renal hamartomas; and
  • sclerotic bone lesions.

For genetic diagnosis, a pathogenic variant in TSC1 or TSC2 will also confirm TSC.

Genetics

  • TSC1 and TSC2 are tumour suppressor genes that have a critical role in the inhibition of the mTOR cell growth and proliferation pathway. TSC is caused by heterozygous loss-of-function pathogenic variants in either the TSC2 or TSC1 gene, which result in constitutive activation of the mTOR pathway and cause benign tumour growth in multiple organs and neuropsychiatric symptoms.
  • Pathogenic variants in the TSC2 gene are the cause of most cases of TSC, and typically result in a more severe phenotype.
  • In around 15% of those with a clinical diagnosis, a pathogenic variant in TSC1 or TSC2 is not identified. These individuals may be mosaic, so deep sequencing of blood or another tissue, such as a skin biopsy, may be useful.

For further information about genomic testing, see Presentation: Clinical suspicion of tuberous sclerosis complex.

Inheritance and genomic counselling

  • TSC is an autosomal dominant condition. Genomic testing of the affected individual and their parents is recommended, particularly as the phenotypic spectrum is wide and mildly affected parents may not have been identified clinically.
  • If one of the parents is affected, the recurrence rate in a future pregnancy (and chance of existing siblings having the condition) will be 50%. If neither parent is found to have the same gene change identified in their child (which is therefore presumed to have arisen de novo, something that accounts for 70% of cases), the recurrence probability is low (approximately 2%, with residual risk reflecting the possibility of constitutional (germline) mosaicism).
  • For most individuals with TSC, the offspring probability is 50%. As a result of significant inter- and intra-familial variation in expressivity, children may be affected to a greater or lesser extent than their parent.
  • For mosaic individuals (in whom the pathogenic variant is not present in all cells), the offspring probability may be less than 50% but is not possible to quantify, because the chance is determined by the proportion of affected germ cells (egg or sperm).

Management

Management of children with TSC is complex and should be delivered via a multidisciplinary team. Screening for all clinical manifestations of the condition is recommended, together with ongoing surveillance.

mTOR inhibitors are increasingly considered as treatment options, though they are not offered in all centres. For some indications (such as subependymal giant cell astrocytomas, angiomyolipomasis and refractive epilepsy), a clinical commissioning policy should be put in place. Other uses of mTOR inhibitors may be considered, such as for cardiac rhabdomyomas, and topical mTOR inhibitors for angiofibroma may be available through individual funding requests.

Resources

For clinicians

References:

For patients

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  • Last reviewed: 16/05/2023
  • Next review due: 16/05/2025
  • Authors: Dr Danielle Bogue
  • Reviewers: Dr Frances Elmslie, Dr Ellie Hay, Dr Emile Hendriks, Dr Terri McVeigh