Tutorial 20th. March 2023

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35	SBA. Fragile X syndrome
36	Role-play. Teach an FY1 the basics of audit
37	Role-play. Explain balanced translocation to FY1
38	EMQ. Edward syndrome

 

35.         EMQ. Fragile X syndrome.

Abbreviations.

AMH:            anti-Müllerian hormone

FXS:               Fragile X syndrome

FXTAS:          Fragile X tremor ataxia syndrome

HFEA:            Human Fertilisation and Embryology Authority

PIGD:            pre-implantation genetic diagnosis.

POF:              premature ovarian failure (now known as POI)

POI:               premature ovarian insufficiency

TR:                 trinucleotide repeat

TTR:               tetranucleotide repeat

 

Question 1. Which, if any, of the following are features of FXS in males?

Option List

A	autism
B	epilepsy
C	hyper-extensible joints
D	learning difficulty
E	post-pubertal macroorchidism

Question 2. Which, if any, of the following are features of FXS in females?

Option List

A	autism
B	epilepsy
C	hyper-extensible joints
D	learning difficulty
E	post-pubertal ovarian enlargement

Question 3. Why are women thought to be less affected by FXS than men?

Option List

A	two X chromosomes dilute the effect of an affected X chromosome
B	leonisation
C	lionisation
D	lyonisation
E	none of the above

Question 4. How common is FXS in males?

Option List

A	1 in 1,000
B	1 in 4,000
C	1 in 8,000
D	1 in 20,000
E	1 in 100.000

Question 5. How common is FXS in females?

Option List

A	1 in 1,000
B	1 in 4,000
C	1 in 8,000
D	1 in 20,000
E	1 in 100.000

Question 6. Which gene is implicated in the causation of FXS?

Option List

A	fragile X mental retardation 1
B	fragile X mitochondrial recognition 1
C	fragile X 1
D	the gene has not yet been identified
E	none of the above

Question 7. Which is the leading hereditary cause of learning difficulty?

Option List

A	Down’s syndrome
B	fragile X syndrome
C	galactosaemia
D	homocystinuria
E	phenylketonuria

Question 8. Which is the most common genetic cause of autism?

Option List

A	Down’s syndrome
B	fragile X syndrome
C	galactosaemia
D	homocystinuria
E	phenylketonuria

Question 9. Which mode of inheritance occurs with FXS?

Option List

A	autosomal dominant
B	autosomal recessive
C	X-linked dominant
D	X-linked recessive
E	none of the above

Question 10. What is the story about trinucleotide repeats and FXS? What are TRs? Which TRs are

involved with FXS? How are TRs categorised in relation to FXS?

There is no option list – just write your Answers.

FXS is due to repeats of the triplet CGG, cytosine-guanine-guanine.

Gene	Number of repeats	Phenotype
Normal	5 to 44	Normal
Gray zone	45-58	Normal
Premutation	59-199	Normal
Full mutation	≥ 200	FXS

Question 11. What is the FXS premutation? What are its key features?

There is no option list – just write your Answers.

Answer.

Females

Males

POI GHR says 20% have overt POI with menopause by the age of 40, compared with a 1% risk in other women. NORD says 21%. Others have ‘occult’ POI with reduced fertility but normal cycles. A woman with POI has a 2-4% of having the FX premutation – NORD says 2%. If there is a family history of POI, the figure is up to 15%. ~ 90% of POI has no identified cause and the FX premutation carrier status is the most common known cause. The premutation may expand to the full mutation when handed on to a son, giving him full-blown FXS. It is handed on intact to daughters, giving them a 50:50 risk of getting it. The premutation predisposes women to anxiety, depression and social awkwardness.

FXTAS which classically develops from the 60s on. Many men were ‘high flyers’ in their early days. There is some evidence of mental deterioration before the tremor and ataxia are apparent. With tremor and intellectual decline, it has features of Alzheimer’s and Parkinsonism. It is thought that it is underdiagnosed in the elderly with these conditions.

 

Repeat	Condition
GAA	Friedreich ataxia
CGG	Fragile X syndrome
CAG	Huntington disease
CTG	Myotonic dystrophy Type 1
CCTG	Myotonic dystrophy Type 2
CTG	Spinocerebellar ataxia Type B

Question 12. What is the importance of the AGG triplet?

Option List

A	it is the sequence analine-guanine-guanine
B	it normally occurs after every 9 or 10 CGG repeats
C	it promotes stability of the CGG repeats
D	high levels of AGG ­ the risk of expansion of FXS premutation to > 200
E	low levels of AGG ­ the risk of expansion of FXS premutation to > 200
F	it has no importance in relation to FXS.

Question 13. A woman has FXS. What is her approximate risk of POI?

Option List

A	0.1%
B	1.0%
C	5.0%
D	10%
E	20%
F	none of the above

Question 14. A woman is a carrier of the FX pre-mutation. What is her approximate risk of POI?

Use the option list in the previous question.

Question 15. A woman develops POI. What is the chance that she has FXS?

Option List. There is none to make you think.

Question 16. A woman develops POI. What is the chance that she is a carrier of the FXS

premutation?

Option List. There is none to make you think.

Question 17. A woman develops POI. She has a 1^st. degree relative with POI. What is the chance that

she has FXS?

Option List. There is none to make you think.

Question 18. A woman develops POI. She has a 1^st. degree relative with POI. What is the chance that

she is a carrier of the FXS premutation?

Option List. There is none to make you think.

 

Fragile X syndrome: an overview Bambang et al. This is open access so reproduced here.

TOG 2011. Volume 13. Issue 2.

Fragile X syndrome (FXS).

1.     is the most common cause of learning difficulty.                                                       False / True

2.     is an X-linked dominant disorder.                                                                                

With regard to women with FXS,

3.     the phenotype is worse than in men.                                                                           False / True

4.     if they have the full mutation, they are more likely to have a normal IQ than autistic features.

With regard to the genetics of FXS,

5.     women with 100 trinucleotide repeats are at higher risk of POI than those with 60.         False / True

6.     equal numbers of female & male carriers of the premutation are affected by FXTAS.

                                                                                                                                                      False / True

With regard to POI and FXS,

7.     up to 25% of women with the fragile X premutation develop POI.                         False / True

8.     measurement of levels of AMH is a valid test for assessing risk of POI.                     False / True

9.     women with POI have a 5-10% chance of spontaneous pregnancy.                       False / True

With regard to testing for FXS,

10.   cell-free fetal DNA testing in maternal blood at 11 weeks is available for identifying the fragile X premutation.                                                                                                               False / True

11.   cascade screening involves testing within families of affected individuals.                             False / True

12.   the HFEA allows preimplantation genetic diagnosis of FXS.                                     False / True

With regard to fragile X tremor ataxia syndrome,

13.   Parkinson’s disease is one of the recognised differential diagnoses.                     False / True

With regard to testing for FXS,

14.   PIGD allows distinction between the pre- and full FMR-1mutations.                     False / True

With regard to FXS,

15.   the mother and daughters of a normal transmitting father are obligate carriers.      False / True

16.   women with the syndrome are at a greater risk of developing depression compared with the general population.                                                                                             False / True

17.   where there are larger numbers of repeat trinucleotides, there is an increased tendency for these repeats to expand in the offspring, causing them to have earlier onset or more severe clinical effects.                                                                                                             False / True

18.   it is a recognised cause of macro-orchidism before and after puberty.                     False / True

19.   men with the syndrome are known to have spermatozoa containing the FMR-1mutation.

  False / True

20.   in families of women with FXS, carriers of the premutation are known to have irregular menses and shorter cycles than non-carriers.                                                                        False / True

 

36.         Role-play. Teach an FY1 the basics of audit.

Candidate’s instructions.

You are the SpR on call for the labour ward. It is a quiet afternoon: all the patients are healthy and in normal labour. Dr. Jane Jones has started in the department as a new FY1. She is keen to specialise in O&G and has already passed the Part 1 examination. A measure of her enthusiasm is that she has asked her consultant if she can be involved in doing an audit, but she is aware that she knows little about it. Her consultant happens to be the consultant on duty for the labour ward and has asked you to ensure that she has enough knowledge to be a useful member of a team conducting an audit.

 

 

37.         Role-play. Explain balanced translocation to FY1.

Candidate’s instructions.

You are the registrar on duty for the labour ward. It is quiet and the consultant has asked you to explain balanced translocation to the FY1, saying it will be good preparation for the Part 3 exam that you have applied to sit.

 

38.         EMQ. Edward syndrome.

Abbreviations.

ES:            Edward syndrome. T₁₈.

DS:           Down syndrome.    T₂₁.

MSAFP:   maternal serum α-feto-protein.

PAPP-A:   pregnancy-associated plasma protein-A.

PS:            Patau syndrome.    T₁₃.

Some of the questions are not true EMQs as there may be > 1 correct answer. The use of ‘is’ or ‘are’ usually indicates which are or are not true EMQs.                

Question 1.             Which, if any, of the following are features of ED.

Option list.

A	abnormal head shape
B	atrial septal defect
C	camptodactyly
D	cleft lip
E	clenched fingers
F	corpus callosum hypoplasia
G	cryptorchidism
H	exomphalos
I	gastroschisis
J	IUGR
K	large ears
L	low birthweight
M	macroorchidism
N	micrognathia
O	myelomeningocoele
P	omphalocoele
Q	overlapping fingers
R	rocker bottom
S	none of the above

Question 2.             Which of the following statements is true?

Option list.

A	ES is the most common autosomal trisomy
B	ES is the 2nd. most common autosomal trisomy
C	ES is the 3rd. most common autosomal trisomy
D	ES is the 4th. most common autosomal trisomy
E	none of the above

Question 3.             What is the approximate incidence of ED in neonates?

Option list.

A	1 in 1,000
B	1 in 2,000
C	1 in 5,000
D	1 in 10,000
E	1 in 100,000
F	none of the above

Question 4.             Which, if any, of the following are true in relation to ES and screening tests in the 1^ST. and 2^nd. trimesters?

Option list.

A	β-hCG is increased
B	β-hCG is normal
C	β-hCG is decreased
D	PAPP-A is increased
E	PAPP-A is normal
F	PAPP-A is decreased
G	inhibin A is increased
H	inhibin A is normal
I	inhibin A is decreased
J	MSAFP is increased
K	MSAFP is normal
L	MSAFP is decreased
M	nuchal translucency is increased
N	nuchal translucency is normal
O	nuchal translucency is decreased
P	unconjugated oestriol  is increased
Q	unconjugated oestriol  is normal
R	unconjugated oestriol  is decreased

Question 5.             Which, if any, of the following are true in relation to ES and choroid plexus cysts?

Option list.

A	CPC are not more common in ES
B	CPCs are the most frequent reason for suspecting ES
C	CPCs are seen in ≥ 50% of fetuses with ES
D	CPC + another anomaly give a high risk of ES
E	CPCs persist longer in ES
F	none of the above

Question 6.             What % of neonates with T18 survive to 1 year of age.

Option list.

A	< 1 %
B	1-5%
C	6-10%
D	10-15%
E	> 15%