Tuberous Sclerosis a multisystem genetic condition

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Tuberous Sclerosis- a multisystem genetic
condition

• Diane Stirling
• Clinical Genetics Department
• Western General Hospital

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Tuberous Sclerosis

• Clinical presentation
• Diagnosis
• Genetic inheritance
• Molecular basis
• Recent research
• TS Video

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Tuberous Sclerosis

• Autosomal dominant condition
• Prevalence of 1 in 6,000
• Multisystem development of hamartomatous lesions
• Variable expession
• Due to mutations in two genes
• (TSC1 and TSC2)

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Systems

• Skin gt90
• Central nervous system gt80
• Kidneys 70
• Heart 60
• Lung 1 -6
• Eyes 25 - 50
• Liver 25
• Skeletal

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Skin Involvement

• Hypomelanotic macules
• Ash Leaf patches
• Most common skin lesion
• 80 - 97
• May not be visible in normal light
• Best seen under UV light (Woods light)

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• Facial angiofibromas
• Adenoma sebaceum
• Rare before 2 years
• 47 - 90
• Butterfly distribution

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• Shagreen patches
• Usually after 2 years
• Leathery appearance
• 48 - 52
• Ungual fibroma
• 20 - 50

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• Forehead fibrous plaques
• 10 - 40
• Maybe present shortly after birth
• Usually appears later
• Molluscum fibrosum
• Skin tags
• Frequently present

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• CNS involvement
• Subependymal Nodules
• 75 - 90
• Cortical tubers
• 87 - 92
• Best seen on MRI
• ?association with learning difficulties

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• Subependymal giant cell astrocytoma
• 6 - 14
• Complications
• Obstructive hydrocephalus
• Raised ICP
• Neurological deficit

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Epilepsy

• 65 - 80 of affected individuals
• Onset is often in the first year of life,
  presenting with infantile spasms
• Partial or generalised
• Seizures can be very difficult to control
• Early treatment of seizures may prevent the
  development of learning disability

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Learning Disability

• Occurs in 40 - 50
• Only reported in association with seizures
• Boys gt Girls
• Early control of seizures may help in
  ameliorating learning disability

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Behavioural Difficulties

• Most common in those with a Learning Disability
• 50 of which display autistic features
• Hyperactivity and attention deficit
• Aggressive, destructive behaviour and self-harm
• Adolescence
• reduction in hyperactivity
• improvement in autistic features
• Can be the most difficult of all the TS symptoms
  for carers to manage

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• Renal involvement
• Angiomyolipomas
• 55 - 70
• lt1 are Malignant

• Renal cysts
• 20 - 25
• May be associated with
• polycystic kidney disease

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• Cardiac involvement
• Rhabodomyomas
• 47 - 67
• Present at birth
• Regresses with time

• Eye involvement
• Phakomas
• 25 - 50

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Variable Expression
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Tuberous Sclerosis - Diagnosis

• Clinical Examination
• Skin (including a Woods light examination)
• Teeth
• Nails
• Investigations
• Cranial CT scan or MRI
• Renal Ultrasound
• Liver Ultrasound

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Dominant Inheritance
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Autosomal Dominant Inheritance
Affected
Unaffected

• involvement of more than one generation
• male to male transmission
• males and females affected equally

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New Mutation

• 2/3 sporadic
• 1/3 familial
• Therefore in the majority of cases there is often
  no family history of the disorder

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Non-penetrance

• When the gene carrier does not manifest the
  conditions clinical features
• Give rise to the skip generation

• Initially thought to occur in TCS
• Using modern day standards of investigation the
  penetrance thought to be 100

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Recurrence risk

• Affected individual
• 50 recurrence risk
• Parents of an affected individual
• if no diagnostic signs are demonstrated
  recurrence risk reduces to 1 - 2

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Tumour Suppressor Genes

• both TSC1 TSC2 are tumour suppressor genes
• function is to control cell growth
  proliferation
• genes may be inactivated by mutations allowing
  tumours to develop

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Two Hit Mechanism
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Molecular Basis of TS

• TSC2
• Chromosome 16p13
• Tuberin
• Most mutations are unique

• TSC1
• Chromosome 9q34
• Hamartin
• Most mutations are unique

• Mutation screening with sensitivity of 90

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Genotype-Phenotype Correlations

• No specific clinical feature which was more
  common to one gene than the other
• ? role of TSC2 in pathogenesis of pulmonary LAM
• Patients with TSC2 mutations have tendency for
  more severe clinical picture

• ? patients with seizures
• ? patients with learning
• difficulties
• ? no. of cortical tubers
• in patients

• ? patients with
• subependymal nodules
• ? patients with large renal
• cysts
• ? patients with Renal AML

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Summary

• TS is still a clinical diagnosis
• Fully penetrant condition
• Wide range of expressivity
• Require formal investigative protocol to ensure
  proper examination of relatives
• Patients with TSC2 mutations have tendency for a
  more severe clinical picture

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Future Developments

• General
• further study into the function/role/interactions
  of Hamartin and Tuberin
• Improvement of mutation analysis techniques to
  allow for wider access of molecular services
• Local
• TS2000 study
• Paediatric TS clinic

The Last Slide !!
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Primary Diagnostic Criteria

• Facial angiofibromas
• Ungual fibromas
• Calcified retinal hamartomas
• Multiple cortical tubers
• Multiple subependymal glial nodules
• (Multiple bilateral renal AML)
• (Forehead fibrous plaque)
• (Shagreen patch)

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Secondary Diagnostic Criteria

• Typical hypomelanic macules
• Bilateral polycystic kidneys
• Pulmonary lymphangiomyomatosis
• Cardiac rhabdomyoma
• Single renal angiomyolipoma
• Multiple subcortical hypomyelinated lesions or
  wedge shaped sub/cortical calcification