Commoner Non-Cancer Genetic Disorders: Part 2

Question 1

Neurofibromatosis Type 1 (NF1)

1. clinical features? [6]
2. possible complications? (increased risk of…) [4]
3. what 3 tumours are NF1 patients at increased risk of developing? [3]
4. genetic basis? [3]

Answer 1

1. clinical features:
   
   • café au lait macules (coffee-coloured patches)
   • neurofibromas (lumps)
   • short stature
   • macrocephaly (large head)
   • Lisch nodules in the eyes
   • learning difficulties (in 30%)
2. possible complications:
   
   • hypertension
   • scoliosis requiring surgery
   • pathological tibal fractures
   • significant tumours
3. increased risk of tumours…
   
   • phaeochromocytomas (tumour of adrenal gland)
   • sacromas (tumour of connective tissue)
   • optic pathway gliomas (tumour in brain near optic nerve)
4. genetic basis:
   
   • autosomal dominant
   • very variable expressivity due to:
     
     • modifier genes for NF1
     • environmental factors (smoking/radiation)

Question 2

Duchenne & Becker Muscular Dystrophy

1. define DMD/BMD [1]
2. mode of inheritance? [1]
3. what is the difference between the genetic basis of Duchenne and Becker’s and how does this relate to the severity of each of the diseases? [6]
4. general pathogenesis? [3]

Answer 2

1. weakness and wasting of certain muscles
2. autosomal recessive
3. differences between Duchenne and Becker’s:
   
   • Duchenne DMD:
     
     • frameshift mutation
     • results in dystrophin not be produced properly, if at all
     • severe condition
   • Becker’s DMD:
     
     • in frame mutation
     • dystrophin is produced, but it is shorter and less functional
     • less severe condition
4. general pathogenesis:
   
   • dystrophin forms a link between F-actin intracellularly and the dystroglycan complex
   • if a fault arises, creatinine kinase (CK) leaks out of damaged muscle fibres into the serum
   • boys with DMD will have significantly increased levels of serum creatinine kinase from birth before any other symptoms are noticeable

Question 3

Fragile X Syndrome

1. definition? [1]
2. genetic basis? [2]
3. differences in phenotypes between males and females? [2]

Answer 3

1. inherited learning disability
2. x-linked recessive with genetic anticipation
3. if the full mutation is present (>200 repeats):
   
   • phenotype in males = severe
   • phenotype in carrier females = occasional but mild

Question 4

Down’s Syndrome:

1. Down’s Syndrome is trisomy ____? [1]
2. what is significant about 14:21 translocation in Down’s Syndrome? [1]
3. clinical features? [3]

Answer 4

1. trisomy 21
2. if translocation present, then it means the condition was inherited from one of the parents, hence increased risk of further children being affected
3. clinical features:
   
   • learning difficulties
   • heart malformations
   • hyperthyroidism

Question 5

Edward’s Syndrome:

1. Edward’s Syndrome is trisomy ____? [1]
2. clinical features? [4]

Answer 5

1. trisomy 18
2. clinical features:
   
   • small chin
   • clenched hands with overlapping fingers
   • malformations of heart, kidney and other orgnas
   • if survive the 1st year, generally have profound learning difficulties

Question 6

Patau Syndrome

1. Patau Syndrome is trisomy ____?
2. clinical features? [7]

Answer 6

1. trisomy 13
2. clinical features:
   
   • congenital heart disease
   • high mortality rate (50% die within first month)
   • cleft lip and palate
   • microphthalmia (abnormally small eyes with malformations)
   • abnormal ears
   • clenched fists
   • post-axial polydactyly (extra little finger)

Question 7

General Pathogenesis of Trisomy’s:

1. general cause of trisomy’s? [1]
2. trisomy’s are more frequent with increased/decreased (choose one) maternal age [1]

Answer 7

1. usually arise due to maternal non-dysjunction in meiosis
   
   • i.e. failure of normal separation of 2 chromosomes
2. more frequent with increased maternal age