Genetics

Question 1

What chromosomal pattern is seen in Klinefelter’s disease?

Answer 1

47 XXY (males)

Question 2

Describe the epidemiology of Klinefelter’s disease

Answer 2

1 in 1000 live male births

Question 3

Give the presentation of Klinefelter’s syndrome in children

Answer 3

1. Clumsiness
2. Mild learning difficulty (still within normal range but IQ slightly reduced)
3. Self obsessed behaviour

Question 4

Give the presentation of Klinefelter’s syndrome in adults

Answer 4

1. Taller than average
2. Long limbs
3. Gynaecomastia
4. Infertility (azoospermia - lack of sperm in semen)
5. Hypogonadism (small, soft testes)
6. Increased risk of breast cancer, osteoporosis, leg ulcers)

Question 5

Give the management of Klinefelter’s syndrome

Answer 5

1. Testosterone - given from puberty onwards to help with development of secondary sexual characteristics

Question 6

Give the inheritance pattern in Marfan syndrome

Answer 6

1. Autosomal dominant connective tissue disorder

Question 7

What is the expected life expectancy with Marfan syndrome?

Answer 7

60 years

Question 8

Describe the pathophysiology of Marfan syndrome

Answer 8

1. Mutilation in fibrillin-1 gene
2. Results in decreased extracellular microfibril production
3. Results in degradation of elastic fibres

Question 9

Describe the presentation of Marfan syndrome

Answer 9

1. Long limbs, tall
2. Long, spindly fingers (thumb extends beyond the edge of clenched fist)
3. Upward dislocation of lens of the eye
4. Pectus deformity
5. Aortic dissection/dilation
6. Dural ectasia (dilation of neural canal)
7. Mitral valve prolapse
8. Joint hypermobility

Question 10

Describe the diagnosis of Marfan syndrome

Answer 10

1. Clinical

Question 11

Describe the management of Marfan syndrome

Answer 11

1. Incurable - reduce risk of dissection
2. Beta blockers - reducing pressure in the aortic root as negatively ionotropic
3. Annual echocardiogram - surgically manage excessive aortic dilation

Question 12

How does homocystinuria differ from Marfan syndrome?

Answer 12

Homocystinuria:
1. Homocysteine in urine
2. Heart not usually affected
3. Downward dislocation of lens
4. Reduced mental ability
5. Responds to pyridoxine

Question 13

Describe the inheritance pattern of cystic fibrosis

Answer 13

Autosomal recessive

Question 14

Describe the pathophysiology of cystic fibrosis

Answer 14

1. Mutation in long arm of chromosome 7 - affecting gene coding for cystic fibrosis transmembrane regulator (a chloride channel)
2. CFTR allows chloride out of cell (in presence of cAMP) into the lumen of airways/pancreatic ducts
3. Causes increased reabsorption of sodium from lumen, causing reduced excretion of water into the lumen
4. This causes viscous mucus which blocks pancreatic ducts

Question 15

Give the presentation of cystic fibrosis

Answer 15

1. Child age 0-2 years
2. Recurrent chest infection (may cause bronchiectasis and abscess formation)
3. Large, offensive stools (plus steatorrhoea)
4. Failure to thrive
5. Meconium ileus (meconium not broken down due to pancreatic insufficiency)
6. Extended period of neonatal jaundice
7. Diabetes mellitus (in older)

Question 16

Give the examination findings seen in cystic fibrosis

Answer 16

1. Chest hyperinflation
2. Inspiratory crepitations
3. Expiratory wheeze
4. Clubbing
5. Hepatomegaly
6. Nasal polyps

Question 17

Give the diagnostic investigations for cystic fibrosis

Answer 17

1. Sweat test - chloride ions in sweat measured - excess chloride indicates CF
2. Faecal elastase - if low is diagnostic of pancreatic insufficiency
3. Guthrie heel prick (newborns)

Question 18

Describe the management of cystic fibrosis

Answer 18

1. Oral pancreatic enzymes
2. Good nutrition
3. PPI (facilitates optimum duodenal pH for pancreatic enzymes)
4. Prophylactic antibiotics (e.g. flucloxacillin) - to prevent resp. infection
5. Mucolytics
6. Nebulised saline
7. Ursodeoxycholic acid to prevent hepatic complications
8. Postural drainage

Question 19

Describe the inheritance pattern seen in fragile X syndrome

Answer 19

X-linked recessive

Question 20

Describe the epidemiology of fragile x syndrome

Answer 20

1. The most common inherited cause of learning difficulty
2. Seen in 1 in 5000 males

Question 21

Describe the clinical presentation of fragile x syndrome

Answer 21

1. Facial features: high forehead, large ears, long face, prominent jaw
2. Large testes
3. Moderate to severe learning difficulty
4. Hyperextensible joints
5. Mitral valve prolapse

Question 22

Describe the inheritance pattern of Haemophilia A

Answer 22

X-linked recessive

Question 23

Describe the pathophysiology of Haemophilia A

Answer 23

Factor VIII deficiency

Question 24

Describe the presentation of Haemophilia A

Answer 24

1. Petechial haemorrhage or bruising
2. Haematoma and haemarthrosis
3. Excessive bleeding (e.g. after dental procedures, venepuncture etc.)
4. Intracranial haemorrhage
5. Haematuria

Question 25

Describe the diagnosis of Haemophilia A

Answer 25

1. Factor VIII assay
2. Activated partial thromboplastin time (APTT)
3. FBC (especially after bleed)

Question 26

Describe the management of Haemophilia A

Answer 26

1. Prevention of acute bleed - factor VIII infusion, avoid NSAIDs, avoidance of risky behaviour (e.g. Contact sport)
2. Management of acute bleed - administer factor VIII, FFP, TXA (antifibrinolytic)