Tutorial 7th. August 2023

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16	Role-play. Role-play. Obstetric history. Take & present the history + plan
17	Structured conversation. Topic revealed during the tutorial.
18	EMQ. Fragile X syndrome
19	SBA. Lynch syndrome

 

16.      Role-play.

I’ll send the topic just before the tutorial so that you don’t have time to prepare anything.

 

17.      Structured conversation.

The examiner will ask a series of questions on a clinical topic.

 

18.      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.

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.

 

The following TOG questions are open access, so reproduced here.

Fragile X syndrome: an overview Bambang et al. 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 develop 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 FXS have greater risk of depression than 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 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

 

19.      Lynch syndrome.

Abbreviations

CRC:              colorectal cancer.

EC:                 endometrial cancer.

IBD:               inflammatory bowel disease: Crohn’s & ulcerative colitis.

IDDM:           insulin-dependent diabetes mellitus.

Ls:                  Lynch syndrome.

MLH:             mutL-homolog family of DNA, mismatch repair genes.

MMR:           mismatch repair.

MSH:             mutS homolog family of DNA, mismatch repair genes.

Question 1.        What is Lynch syndrome?

Option List

A	auto-immune condition leading to reduced factor X levels in blood
B	hereditary condition which increases the risk of many cancers, particularly breast
C	hereditary condition which increases the risk of many cancers, particularly breast & colorectal
D	hereditary condition which increases the risk of many cancers, particularly colorectal & endometrial
E	none of the above

Question 2.        How is Lynch syndrome inherited?

Option List

A	it is an autosomal dominant condition
B	it is an autosomal recessive condition
C	it is an X-linked dominant condition
D	it is an X-linked recessive condition
E	none of the above

Question 3.        Which, if any, of the following genes can cause Lynch syndrome?

Option List

A	MLH1 + MLH2 + MOH1
B	MLH1 + MLH2 + MSH1
C	MLH1 + MLH2 + MSH6
D	MLH1 + MSH2 + MSH6
E	None of the above

Question 4.        Mutations of which 2 of the following genes cause most cases of Lynch syndrome?

Option List

A	MLH1 + MLH2
B	MLH1 + MSH1
C	MLH1 + MSH2
D	MLH2 + MSH1
E	MLH2 + MSH2

Question 5.        What is the approximate prevalence of Ls in the UK population?

Option List

A	1 in 50
B	1 in 100
C	1 in 1,000
D	3 in 1,000
E	none of the above

Question 6.        Approximately what % of individuals with Ls have had the diagnosis established?

Option List

A	< 5%
B	5 -10%
C	10-20%
D	20-30%
E	>30%

Question 7.        Which, if any, of the following conditions are associated with an ↑ risk of Ls?

Option List

A	acromegaly + Addison’s disease + coeliac disease + IBD + IDDM
B	acromegaly + disease + anosmia + coeliac disease + IBD
C	acromegaly + IBD + IDDM
D	acromegaly + IBD
E	Addison’s disease + anosmia + coeliac disease + IBD + IDDM
F	acromegaly + Addison’s disease + anosmia + coeliac disease + IBD + IDDM
G	none of the above

Question 8.        Which 2 cancers are most likely in women with Lynch syndrome?

Option List

A	breast + bowel
B	breast + pancreas
C	breast + endometrium
D	bowel + cervix
E	bowel + endometrium
F	bowel + ovary
G	bowel + pancreas
H	endometrium + ovary

Question 9.        What does NICE recommend about screening for Lynch syndrome for the population

with no personal history of colorectal cancer?

Option List

A	offer screening to those aged < 50 years with  ≥ 1 affected 1st.O relative
B	offer screening to those aged < 60 years with ≥ 1 affected 1st.O relative
C	offer screening to those with ≥ 1 affected 1st.O relative aged < 50 years at diagnosis
D	offer screening to those with ≥ 1 affected 1st.O relative aged < 60 years at diagnosis
E	none of the above

Question 10.    What does NICE recommend in relation to screening for Lynch syndrome in those with

a new diagnosis of colorectal cancer?

Option List

A	offer screening to everyone, regardless of age and family history
B	offer screening to those aged < 50 years at diagnosis
C	offer screening to those aged < 60 years at diagnosis
D	offer screening to those aged < 50 years at diagnosis with + ≥ 1 affected 1st.O relative
E	offer screening to those aged < 60 years at diagnosis with + ≥ 1 affected 1st.O relative

Question 11.    What does NICE recommend about screening for Lynch syndrome for the population

with no personal history of thyroid cancer?

Option List

A	offer screening to those aged < 50 years with  ≥ 1 affected 1st.O relative
B	offer screening to those aged < 60 years with ≥ 1 affected 1st.O relative
C	offer screening to those with ≥ 1 affected 1st.O relative aged < 50 years at diagnosis
D	offer screening to those with ≥ 1 affected 1st.O relative aged < 60 years at diagnosis
E	none of the above

Question 12.         What does NICE recommend in relation to screening for Lynch syndrome in those

with a new diagnosis of thyroid cancer?

Option List

A	offer screening to everyone, regardless of age and family history
B	offer screening to those aged < 50 years at diagnosis
C	offer screening to those aged < 60 years at diagnosis
D	offer screening to those aged < 50 years at diagnosis with + ≥ 1 affected 1st.O relative
E	none of the above

Question 13.    What does NICE recommend about screening for Lynch syndrome for the population

 with no personal history of endometrial cancer?

Option List

A	offer screening to those aged < 50 years with  ≥ 1 affected 1st.O relative
B	offer screening to those aged < 60 years with ≥ 1 affected 1st.O relative
C	offer screening to those with ≥ 1 affected 1st.O relative aged < 50 years at diagnosis
D	offer screening to those with ≥ 1 affected 1st.O relative aged < 60 years at diagnosis
E	none of the above

Question 14.    What does NICE recommend in relation to screening for Lynch syndrome in those with

a new diagnosis of endometrial cancer?

Option List

A	offer screening to those aged < 50 years with  ≥ 1 affected 1st.O relative
B	offer screening to those aged < 60 years with ≥ 1 affected 1st.O relative
C	offer screening to those with ≥ 1 affected 1st.O relative aged < 50 years at diagnosis
D	offer screening to those with ≥ 1 affected 1st.O relative aged < 60 years at diagnosis
E	none of the above

Question 15.    What does NICE recommend about screening for Lynch syndrome for the population

with no personal history of colorectal cancer?

Option List

A	offer screening to those aged < 50 years with  ≥ 1 affected 1st.O relative
B	offer screening to those aged < 60 years with ≥ 1 affected 1st.O relative
C	offer screening to those with ≥ 1 affected 1st.O relative aged < 50 years at diagnosis
D	offer screening to those with ≥ 1 affected 1st.O relative aged < 60 years at diagnosis
E	none of the above

Question 16.    What does NICE recommend in relation to screening for Lynch syndrome in those with

a new diagnosis of colorectal cancer?

Option List

A	offer screening to everyone, regardless of age and family history
B	offer screening to those aged < 50 years at diagnosis
C	offer screening to those aged < 60 years at diagnosis
D	offer screening to those aged < 50 years at diagnosis with + ≥ 1 affected 1st.O relative
E	offer screening to those aged < 60 years at diagnosis with + ≥ 1 affected 1st.O relative

Question 17.    What relationship, if any, exists between Ls and acromegaly?

Option List

A	the risk of Ls is ↓ in those with acromegaly compared with the general population
B	the risk of Ls is ↑ in those with acromegaly compared with the general population
C	the risk of Ls is unchanged in those with acromegaly compared with the general population
D	the risk of Ls in unknown in those with acromegaly
E	none of the above

Question 18.    What is the effect of aspirin consumption on the risk of EC and CRC?

Option List

A	aspirin reduces the risk of EC and CRC
B	aspirin reduces the risk of EC but not CRC
C	aspirin reduces the risk of CRC but not EC
D	aspirin does not reduce the risk of EC or CRC
E	aspirin reduces the risk of EC and CRC, but the risks outweigh the benefits

Question 19.    A healthy woman of 35 years is diagnosed with Ls? What are the key elements of the

National Screening Programme for people with Ls?

There is no option list – just write down everything you know.

Question 20.    Which, if any, of the following were recommendations made by Monahan et al, the 30

experts who wrote to the BMJ in 2017.

Option List

A	creation of a national register of people with Ls
B	creation of a post of Consultant in Ls for each NHS Trust
C	creation of a post of Clinical Champion for Ls in each NHS Region.
D	creation of a post of Clinical Champion for Ls in the DOH.
E	none of the above

With regard to Lynch syndrome,

1.     loss of mismatch repair protein expression on immunohistochemistry of cancer is diagnostic.

True/False

2.     most carriers of the mutation associated with the syndrome know they have the condition.

True/False

3.     the first cancers associated with the syndrome are predominantly endometrial or ovarian cancers.                                                                                                                               True/False

4.     when cancers occur, they have in them an unusually high immune infiltrate.    True/False

With regard to testing for Lynch syndrome,

5.     consent must be sought before definitive germline testing for Lynch syndrome by a trained professional.                                                                                                                       True/False

6.     immunohistochemical staining of tumours for the mismatch repair proteins or microsatellite instability analysis are recognised ways of screening cancers for characteristics suggestive of the syndrome.                                                                                                                     True/False

7.     the National Institute for Health and Care Excellence endorses universal screening of colorectal cancer patients for Lynch syndrome.                                                                               True/False

8.     most gynaecological cancers found to have aberrant mismatch repair immunohistochemical staining will be in those with the syndrome.                                                  True/False

9.     the addition of MLH1 promotor hypermethylation testing in a Lynch syndrome diagnostic pathway improves specificity.                                                                               True/False

Regarding gynaecological surveillance in women with Lynch syndrome,

10.   there is strong evidence to recommend its use.                                                         True/False

11.   this should be offered to women around 25 years of age.                                       True/False

12.   counselling should include education on red flag symptoms of cancer and risk-reducing surgery.

True/False

With regard to risk-reducing strategies for women with Lynch syndrome,

13.   hysterectomy is strongly recommended for all those with the syndrome.               True/False

14.   the timing of risk-reducing surgery depends on the syndrome gene.                     True/False

15.   where possible, a laparoscopic approach is recommended.                                    True/False

16.   aspirin is not recommended as a means of reducing their overall cancer risk.              True/False

Regarding Lynch syndrome-associated gynaecological cancers,

17.   endometrial types that arise as a result of the syndrome have a poorer prognosis than sporadic types.                                                                                                                                 True/False

18.   checkpoint inhibition of the PD-1/PD-L1 pathway has been shown to be very effective in mismatch repair-deficient cancers.                                                                                       True/False

19.   vaccination against these cancers is currently the focus of research.                     True/False

20.   the Manchester International Consensus guideline is a useful reference for gynaecologists managing women with these cancers.                                                                True/False