Multi-system disease

Question 1

What are the possible modes of inheritance in multi-system genetic disorders?

Answer 1

• Chromosomal
  
  • numerical eg trisomy 21
  • structural eg translocations, deletions and microdeletions
• Single gene disorders
  
  • autosomal dominant eg TS, NF1, myotonic dystrophy
  • autosomal recessive eg Cystic fibrosis
  • X- linked eg Duchenne muscular dystrophy
• Multi-factorial
  
  • polygenic
  • environmental factors - diabetes, haemochromatosis

Question 2

Why might a genetic disease have multi-system involvement? (3)

Answer 2

• Several genes with diverse functions are involved (chromosomal)
  
  • extra copies of some or many genes - trisomy, duplications
  • only single copies of some or many genes - monosomy , deletions, microdeletions (contiguous gene syndromes)
• Single gene widely expressed in different tissues
• Single gene has tissue-specific expression but that tissue is an integral part of many different systems

Question 3

What is Neurofibromatosis Type 1 (NF1)/ Von Recklinghausen disease?

Answer 3

A genetic disorder characterised by the development of multiple noncancerous (benign) tumors of nerves and skin (neurofibromas) and areas of abnormal skin color (pigmentation).

• Autosomal dominant
• 1 in 2500-3500

Question 4

What is the diagnostic criteria for NF1?

Answer 4

Need 2+ for diagnosis

• Cafe au lait spots - 6 or more
• Neurofibromas - 2 or more
• Axillary freckling
• Lisch nodules (specks in iris)
• Optic glioma
• Thinning of long bone cortex
• Family history

Question 5

Further features of NF1 not included in the diagnostic criteria

Answer 5

• Macrocephaly - large head
• Short stature
• Dysmorphic features- “Noonan look”
• Learning difficulties
• Epilepsy
• Scoliosis
• Pseudoarthrosis of the tibia
• Raised BP - due to renal artery stenosis or phaechromocytoma
• Neoplasia - CNS (optic gliomas), endocrine

Question 6

Management of NF1

Answer 6

Annual review of affected individuals and at risk children until diagnosis can be excluded (5 years)

• BP
• Spinal examination for scoliosis
• Tibia for unusual angulation
• Visual acuity and visual fields
• Educational assessment
• Ask patient to report any unusual symptoms

Question 7

Which gene has been identified as a cause of NF1?

Answer 7

NF1 is caused by mutations in a gene called NF1, which is found on chromosome 17q (long arm of 17) - tumour suppressor gene

Question 8

How is NF2 different to NF1?

Answer 8

NF2 is on Chromosome 22

The main features of NF2 are:

• acoustic neuromas - benign tumour that develops on the vestibular, or cochlear nerves
  
  • »usually bilateral
• CNS and spinal tumours
• a few Cafe au Lait spots

Question 9

What is Tuberous Sclerosis and what is its classic triad?

Answer 9

An autosomal dominant condition which causes harmartomas to develop in different organs throughout the body

Classic triad:

• Epilepsy
• Learning difficulty
• Skin lesions

Question 10

What genes cause TS?

Answer 10

2 genes on different chromosomes both cause TS with identical phenotypes

• TSC1 and TSC2

Question 11

Clinical features of TS

Answer 11

• Multi-system
• Variable expression
  
  • asymptomatic - severe mental
  • occasionally physical handicap
• Learning difficulty 40% - autism features common
• Seizures 65% - infantile spasms and myoclonic seizures
• Skin lesions - depigmented macules, angiofibromas, fibrous plaque forehead
• Kidney - cysts
• Phakomas in eye
• Rhabdomyomas in heart

Question 12

Investigations done for TS

Answer 12

• Cranial MRI
• Renal USS
• Echocardiogram
• Retinal examination

Question 13

What is myotonic dystrophy?

Answer 13

• A type of genetic muscular dystrophy - the most common type
• Autosomal dominant. It is caused by a CTG triplet repeat mutation which gets worse each generation
• May present with bilateral late-onset cataract
• Causes progressive muscle weakness, stiffness & myotonia (prolonged contraction), low motivation, bowel probs, diabetes mellitus