GENETICS

Questions&Answers
Q-1
A neonate’s chest X-ray shows a double bubble sign. He has low set ears and a
flat occiput. What is the SINGLE most likely diagnosis?

A. Down’s syndrome
B. Fragile X syndrome
C. Turner’s syndrome
D. DiGeorge syndrome
E. Edward’s syndrome

ANSWER:
Down’s syndrome

EXPLANATION:
Down syndrome has many features. Duodenal atresia is one of them that you must
notforget. Double bubble sign indicates duodenal atresia.

For the purpose of PLAB, link these 3 terms closely:

Double bubble sign → Duodenal atresia → Down’s syndrome
It is easy to remember as the all start with the letter “D”.

Down’s Syndrome
Clinical features
- face: upslanting palpebral fissures, epicanthal folds, protruding tongue,small ears,
round/flat face
- flat occiput
- single palmar crease, pronounced 'sandal gap' between big and first toe
- congenital heart defects
- duodenal atresia
- Hirschsprung's disease

Cardiac complications
- atrioventricular septal canal defects
- ventricular septal defects
Later complications
- subfertility
- learning difficulties
- short stature
- acute lymphoblastic leukaemia
- Alzheimer's

COMPARING THE TRISOMIES

These are some of the key features of the trisomies

Features
Patau syndrome (Trisomy 13) Microcephalic
Microphthalmia
Cleft lip and palate
Polydactyly
Scalp defects (cutis aplasia: skin missing from the
scalp)
Edward syndrome (Trisomy 18) Microcephaly
Micrognathia
Prominent occiput
Rocker bottom feet
Clenched hand-index over third; fifth over fourth
Down syndrome (Trisomy 21) Flat occiput
Round/flat face
Epicanthal folds
Single palmar crease
Protruding tongue
Duodenal atresia

Q-2
A 42 year old female presents to you with the concern of ovarian cancer. She has
two older sisters who have both been diagnosed with ovarian cancer and she is
worried that she may have ovarian cancer as well. A pelvic ultrasound was
carried out as part of investigating her symptoms of menorrhagia a month ago
and was unremarkable. What is the SINGLE next best step in management of this
patient?

A. CA 125 level
B. Genetic counselling
C. Abdominal ultrasound
D. Computed tomography scan of the pelvis and abdomen
E. Prophylactic salpingo-oophorectomy

ANSWER:
Genetic counselling

EXPLANATION:
The 2013 Scottish Intercollegiate Guidelines Network (SIGN) guidelines advise that
women with a family history (first-degree or second-degree relative) that appears to
increase their risk of developing ovarian cancer should be referred to a clinical genetics
service for full assessment of risk.

Genetic counselling would be more appropriate here compared to a CA-125 as she has
no symptoms of an ovarian cancer and a pelvic ultrasound scan was seen to be normal.

Any of the following criteria would signify an increased risk for ovarian cancer
• The woman is a known carrier of the BRCA1 or BRCA2 cancer gene mutations
• She has a first-degree or second-degree relative who carries a gene mutation
• Two family members who are first-degree relatives of each other have ovarian
cancer
• One family member has both breast and ovarian cancer

These high risk women should be offered genetic screening and counselling.

Steps to investigate a patient with suspected ovarian cancer:

1. CA 125 test
2. Pelvic and abdominal ultrasound scans
3. CT scan of the pelvis and abdomen
4. MRI scan can be used for pre-operative staging
5. High-risk women may be offered referral for prophylactic salpingo-oophorectomy

Q-3
A mother has a child with 17-alpha-hydroxylase deficiency. She is now pregnant
for the second time. What are the risks of her unborn child having congenital
adrenal hyperplasia?

A. 1:1
B. 1:2
C. 1:4
D. 1:8
E. 2:3

ANSWER:
1:4

EXPLANATION:
Unfortunately this is not the type of question that you figure out using logic. You need to
learn that Congenital Adrenal Hyperplasia is an autosomal recessive genetic disorder.
This means that in order for a child to have the condition, both parents need to have the
recessive gene. This would result in 25% of offspring being normal, 50% of offspring
being carriers and 25% of offspring having the disease in its active form

CONGENITAL ADRENAL HYPERPLASIA

• Autosomal recessive disorder
• Comes in three forms: 21-hydroxylase, 11-hydroxylase or 3-β hydroxysteroid
dehydrogenase deficiency
• Females with classic form: ambiguous genitalia
• Males with classic form: hyperpigmentation, penile enlargement, aldosterone
deficiency
• Males with salt-losing form: typically present at 7-14 days of life with vomiting,
weight loss, lethargy, dehydration, hyponatraemia and hyperkaleima

It is unlikely you would be asked how to treat this disease or the biosynthesis pathways
for the exam. Just know how to identify the various presentations, and remember that it
is an autosomal recessive disorder.

21-hydroxylase deficiency
The most common and is characterized by cortisoldeficiency (with or without
aldosterone deficiency) and androgen excess.
11-beta-hydroxylase deficiency
The second most common and is characterized byaldosterone deficiency which causes
salt-wasting) in early infancy and excesshypertension in childhood and adult life

17-alpha-hydroxylase deficiency
Extremely rare and is characterized by hypertrophyof the adrenal cortex. It presents in
much the same way as 11-beta-hydroxylasedeficiency.

Q-4
An 11 year old has increased laxity of joints and hyperelastic skin. He is noted to
have mild spinal curvature and a blue sclera. What is the SINGLE most likely
diagnosis?

A. Fragile X syndrome
B. Prader-Willi syndrome
C. DiGeorge syndrome
D. Marfan’s syndrome
E. Ehlers-Danlos syndrome

ANSWER:
Ehlers-Danlos syndrome

EXPLANATION:
Ehlers-Danlos syndrome
There are many types of EDS based on different gene mutations affecting the
structureor assembly of different collagens. Many syndromes overlap and it may be
difficult todifferentiate one from the other. But not however, they all share common
features of:
- Hyperelasticity of skin
- Joint hypermobility

Those are the only two signs you need to know for your exam for Ehlers-
Danlossyndrome
Q-5
A 44 year old lady who has polycystic kidney disease is concerned because her
38 year old brother recently died of an intracranial insult. She knows he was not
hypertensive. Wht was the SINGLE most likely cause of her brother’s death?

A. Subdural haematoma
B. Subarachnoid haemorrhage
C. Cerebral infarct
D. Epidural haematoma
E. Dehydration

ANSWER:
Subarachnoid haemorrhage
EXPLANATION:
The key to answer this question is to look for associations. Cerebral aneurysms are
recognized association of polycystic kidney disease. Since polycystic kidney disease
has a genetic component, it is safe to assume that the question writers are trying to hint
that the brother also has polycystic kidney disease. The most serious possible
complication of poylycystic kidney disease is a cerebral aneurysm that ruptures. This
causes a subarachnoid haemorrhage.

Q-6
A 33 year old mother of a child with cystic fibrosis is concerned of her next baby
also having cystic fibrosis. She is with the same partner and they both are
completely healthy. What is the SINGLE most likely probability of their future
child having cystic fibrosis?

A. 1:2
B. 1:4
C. 1:8
D. 1:1
E. No risk

ANSWER:
1:4

EXPLANATION:
Cystic fibrosis (CF) is an autosomal recessive disorder. This means that the parents of
the cystic fibrosis child are carriers.

If a child is born to parents who carry the same autosomal recessive change (mutation),
the child has a 1 in 4 chance of inheriting the abnormal gene from both parents and
developing the disease. The child would have a 50% (1 in 2) chance of inheriting one
abnormal gene. This would make him/her a carrier.

GENETIC INHERITANCE REVIEW BEFORE THE EXAM

It is worth remembering all the common genetic diseases and how they are passed on
to their offspring. This page should be reviewed just before going for the exam to
refresh your memory.

Autosomal recessive
Child has 25% chance of inheriting the genetic condition if BOTH parents are carriers of
the faulty gene.
• Cystic fibrosis
• Sickle cell anaemia
• Thalassaemia

Autosomal dominant
Child has 50% chance of inheriting the genetic condition if ONE parent has the
mutation.
• Huntington
• Neurofibromatosis
• Autosomal dominant polycystic kidney disease

X-linked dominant
Child has a 50% chance of inheriting the genetic condition if MOTHER has the mutation
(MOTHER would also be affected by the disorder). Female child has a 100% chance of
inheriting the genetic condition and male child has 0% chance of inheriting the genetic
condition if FATHER has the mutation (FATHER would be affected by the disorder).
• Fragile X syndrome
If you google image Fragile X syndrome, you would realise that all the pictures are
of male children. Why are the features of Fragile X-syndrome seen more in males
even though females are more often affected (an X-linked dominant condition)?
This is because males display a complete penetrance and therefore almost always
display symptoms of Fragile X syndrome however females display penetrance of
about 50% as a result of having a second normal X-chromosome and so they have
symptoms that are less severe than males.

X-linked recessive
Male child has a 50% chance of inheriting the genetic condition if MOTHER is a carrier.
Female child has a 50% chance of becoming a carrier if MOTHER is a carrier. X-inked
recessive conditions do not affect females to a significant degree as the other X-
chromosome would most likely be normal and can compensate for the mutated
chromosome.
• Haemophilia
• Duchenne muscular dystrophy

CYSTIC FIBROSIS
Cystic fibrosis is an autosomal recessive disorder which induces low salt and chloride
excretion into airways leading to increased viscosity of secretions

Clinical presentation
- Recurrent chest infections (Cough and chronic sputum production)
o Recurrent chest infections may lead to bronchiectasis
- Malabsorption → Leading to:
o Frequent, bulky, greasy stools (Steatorrhoea)
o Failure to thrive
- Pancreas → increased incidence of diabetes mellitus
- Delayed sexual development
- Male infertility, female subfertility
- Salty taste of skin
- Short stature
- Meconium ileus (in neonatal period)

Diagnosis
• Primarily made during newborn screening (Guthrie test)
o All newborn infants in the UK are screened for cystic fibrosis using the heel-
prick test – Majority of them would be identified using this method
o If this is positive, then molecular genetic testign for CTFR gene and sweat test
wuld follow.
• If not picked up by newborn screening and later on develops clinical manifestations
of cystic fibrosis, then perform sweat test or genetic testing for CTFR gene.

Q-7
A 14 year old girl has a recent diagnosis of Turner syndrome. Which of the
following statements are correct in relation to women with Turner syndrome?

A. Turner syndrome females have no learning problems

B. Human growth hormone is not effective in increasing height of girls with
Turner syndrome
C. Oestrogen replacement therapy for Turner syndrome is only started in
adulthood
D. Mother’s age is a strong risk factor
E. Turner syndrome females are able to conceive with assisted reproduction
techniques

ANSWER:
Turner syndrome females are able to conceive with assisted reproduction techniques

EXPLANATION:
Most women with Turner syndrome have normal intelligence however some do still
have learning difficulties especially involving spatial visualization that may be needed for
mathematics. They also may have issues with nonverbal and social skills.

Human growth hormone injections during childhood are used as part of treatment of
Turner syndrome girls to increase height to an average adult height.

Oestrogen replacement therapy is also used to promote development of breast and hips
and to prevent osteoporosis and it is used in childhood.
Advanced maternal age is not a risk factor for Turner syndrome.

Almost all affected women are infertile due to ovarian dysgenesis, but some are able to
conceive with assisted reproduction

AMENORRHOEA
Amenorrhoea is the absence of menstruation. Pathological amenorrhoea is the failure
to menstruate for at least 6 months. Amenorrhoea can be divided into
• Primary amenorrhoea – Lack of menstruation before age 16 years or 14 in the
absence of secondary characteristics
• Secondary amenorrhoea – Cessation of menstrual cycles following established
cycles

Aetiology
• Hypothalamic amenorrhoea
o Most common
o Usually due to low BMI or excessive exercise
• Polycystic ovarian syndrome (PCOS)
• Hyperprolactinaemia
• Premature ovarian failure
o Raised FSH levels
• Anatomical problems
o Usually results in primary amenorrhoea
o Vaginal examinations to rule out imperforate hymen is important
o Pelvic ultrasound also useful to determine the pelvic anatomy (Mullerian
agenesis)
o Anatomical problems can also cause secondary amenorrhoea (Asherman’s
syndrome)
• Thyroid problems
o Both hyperthyroidism and hypothyroidism can cause amenorrhoea

Don’t forget pregnancy as a cause of amenorrhoea

Specifics to look for in the stems

• Short stature – May indicate Turner syndrome
• Hirsutism, acne (androgen excess) – May indicate PCOS or hyperprolactinaemia
• Menopausal symptoms in women before age 40 – May indicate premature ovarian
failure
• Eating disorder – May indicate anorexia nervosa
• Galactorrhoea – May indicate hyperprolactinaemia

Q-8
A 42 year old woman is 16 weeks pregnant. She was late in booking her antenatal
appointments and missed her first trimester scan. She is extremely worried
about an abnormal chromosomal anomaly in her unborn baby as her first child
was born with Down Syndrome. What is the SINGLE most definitive
investigations at this stage?

A. Amniocentesis
B. Chorionic villous sampling
C. Parents karyotyping
D. Transvaginal ultrasound
E. Preimplantation genetic testing

ANSWER:
Amniocentesis

EXPLANATION:
The most appropriate test at this gestation would be an amniocentesis.

Amniocentesis
Amniocentesis is an invasive, diagnostic antenatal test. It involves taking a sample
ofamniotic fluid in order to examine fetal cells found in this fluid.

Amniocentesis is an invasive procedure, diagnostic antenatal test involving taking a

20ml sample of amniotic fluid using a transabdominal needle under ultrasound
guidancein order to examine fetal cells found in this fluid. It is offered after screening
tests haveindicated a high risk of fetal abnormality or in women considered to be at high
risk, forexample if above 35 years old.

Amniocentesis is usually performed at 16 weeks and the risk of fetal loss is 0.5-1%.
Thekaryotype results typically take 3 weeks.

Conditions which may be diagnosed

- Neural tube defects (raised AFP levels in the amniotic fluid)
- Chromosomal disorders
- Inborn errors of metabolism

Timing of amniocentesis
- Early (between 12 and 14+6 weeks of gestation):
o This is not recommended, as it is associated with an increased risk ofmiscarriage
- Mid-trimester (between 15 and 18 weeks of gestation):
o This is the most common time for the procedure.
- Third trimester
o May be undertaken for late karyotyping

AMNIOCENTESIS VS CHORIONIC VILLOUS SAMPLING VS NON INVASIVE

PRENATAL TESTING

INVASIVE PRENATAL TESTING

Amniocentesis Chorionic Villous Sampling
• Samples amniotic fluid • Samples placenta using an ultrasound-guided transabdominal
 using an ultrasound- needle or ultrasound-guided transcervical cannula aspiration
guided transabdominal • Cannot be used to screen for neural tube defects (unlike
needle amniocentesis)
• Usually performed • Usually performed between 11 and 14 weeks (11+0 to 13+6)
between 15 and 18 • Results are obtained within 1 to 2 weeks
weeks of gestation • Because CVS allows diagnosis earlier in pregnancy compared to
• The karyotype results amniocentesis, there is an earlier opportunity to consider
typically take 3 weeks termination of pregnancy in the event of fetal abnormality

NON INVASIVE PRENATAL TESTING

• NIPT looks at fetal cells and fetal DNA circulating in maternal blood
• It is non invasive because the test only involves taking a sample of mother’s blood
• It is now possible to use NIPT to detect chromosomal abnormalities such as Down syndrome and
three of the other common aneuploidies: Edwards syndrome, Patau syndrome and Turner
syndrome
• Certain NIPT tests have detection rate of around 99.9% for Down syndrome and results take only a
few days
• Unfortunately, NIPT is not available on the NHS and is only available privately in the UK at present
• Like the combined test, NIPT is a screening test, and a diagnostic test like a CVS or an
amniocentesis will still be needed to confirm a positive result

Q-9
A 3 year old boy presents with rectal prolapse. He is notd to be below the 5 th
percentile for weight and height. His mother is also concerned because he has a
foul-smelling bulky stool that “floats”. She also states that the child has
developed a repetitive cough over the last few months. What is the SINGLE most
appropriate initial investigation?

A. Endomysial antibody (IgA)

B. Sweat test
C. Barium meal
D. Anti-gliadin antibody (IgA or IgG)
E. Glucose tolerance test

ANSWER:
Sweat test

EXPLANATION:
Sweat testing can confirm the diagnosis of cystic fibrosis and is 98% sensitive. The
rectal prolapse is due to bulky stools which is seen in cystic fibrosis.

Q-10
A 26 year old tall and slender man and his wife have been trying to conceive for
the past 3 years. He has been investigated for primary infertility and his recent
semen analysis is consistent with azoospermia. On examination, he has small,
firm testes. What is the SINGLE most appropriate investigation to be performed
to diagnose his condition?

A. Testosterone
 B. Luteinising hormone (LH)
C. Follicle-stimulating hormone (FSH)
D. Estradiol
E. Karyotyping

ANSWER:
Karyotyping

EXPLANATION:
The likely diagnosis is Klinefelter’s syndrome. While it is true that serum testosterone
islow or low normal and FSH and LH are elevated (FSH >LH) in Klinefelter’s syndrome,
thediagnosis is confirmed by chromosomal analysis. Raised LH and FSH are due to
lack of negative feedback from low levels of circulating testosterone on the pituitary
gland.
The most common indications for karyotyping are hypogonadism and infertility.
Many with known Klinefelter's syndrome are not diagnosed until they are adults.
TheSINGLE best test that confirms diagnosis is a chromosomal analysis.
Klinefelter’s syndrome (XXY)
Findings
- Mental retardation (average IQ 85-90)
- Behavioral problems
- Long limbs ( decreased upper:lower segment ratio)
- Tall and slim
- Hypogonadism
- Infertility
- Gynecomastia

Q-11
A 32 year old female has café au lait spots seen at birth. Axillary freckles started
to appear in her childhood. What is the probability of her child having the same
condition as she has?
A. 1:2
B. 1:4
C. 1:16
D. 3:4
E. No genetic link
ANSWER:
1:2

EXPLANATION:
This lady has neurofibromatosis. The risk of an affected individual with
neurofibromatosis type 1 or 2 transmitting the disease to their child is 50%

Neurofibromatosis
There are two types of neurofibromatosis, NF1 and NF2. Both are inherited in an
autosomal dominant fashion.

Type 1 Type 2
More common form A central form with CNS tumours rather than skin lesions
• Café-au-lait spots • Bilateral acoustic neuromas
• Axillary/groin freckles • Multiple intracranial schwannomas, meningiomas
• Peripheral neurofibromas and ependymomas
• Iris hamartomas (Lisch nodules)
• Scoliosis
• Association with phaeochromocytomas

Q-12
A 4 year old child has progressive muscle weakness and frequent falls. He has a
waddling gait when he attempts to run. He is unable to hop or jump. His motor
milestones seemed to be delayed. What is the SINGLE most likely diagnosis?

A. Duchenne muscular dystrophy

B. Becker’s muscular dystrophy
C. Polymyositis
D. Lambert-Eaton syndrome
E. Polymyalgia rheumatica

ANSWER:
Duchenne muscular dystrophy

EXPLANATION:
Duchenne muscular dystrophy is an X-linked recessive condition which presents in
earlychildhood and inevitably progresses. Some carriers also have symptoms.
Newmutations are common in DMD; this means that female relatives of a child with
DMDare not necessarily carriers of the gene.

Becker's muscular dystrophy (BMD) is similar to the more common muscular dystrophy-
Duchenne muscular dystrophy (DMD) - but the clinical course is milder. As with
DMD,there is muscle wasting and weakness which is mainly proximal. Generally,
walkingdifficulties begin after the age of 16 in Becker's muscular dystrophy. Thus the
mostappropriate answer here is Duchenne’s muscular dystrophy.
Duchenne muscular dystrophy
Presentation:
- PLAB 1 setting: boy comes into clinic by age 4-8 years
- Delayed motor milestone: walking at > 18 months, can’t hold objects
- Inability to run - waddling gait when attempting to do so.
- Gower’s sign, proximal muscle weakness
- +/- Respiratory or cardiac signs/symptoms
- Elevated creatine kinase, AST, ALT

Diagnosis:
- Creatine kinase - initial → (CK levels are very high (10-100 x normal from birth).
- Blood sample and muscle biopsy → genetic testing for dystrophin mutations →PCR
- Neuromuscular assessment → diagnosis severity and determine management
- Genetic testing after a positive biopsy diagnosis of DMD is mandatory

Q-13
A 44 year old woman presents with memory loss, poor concentration and inability
to recognize household objects. She has right-handed involuntary writhing
movement which has just recently started. She reports occasional difficulty in
walking. There is a strong family history with similar symptoms. What is the
SINGLE most likely diagnosis?

A. Friedreich’s ataxia
B. Wilson’s disease
C. Huntington’s disease
D. Motor neuron disease
E. Charcot-Marie-Tooth disease

ANSWER:
Huntington’s disease

EXPLANATION:
The right-handed involuntary writhing movements are called chorea. These
areuncontrollable limb movements. Cognitive abilities are progressively impaired
inHuntington’s which explains the memory loss, poor concentration and the inability
torecognize household objects. A general lack of coordination and an unsteady gait
oftenfollow. The final clue is the strong family history. Huntington’s disease is an
autosomaldominantdisorder. One can imagine either her father or mother with this
disorder.

Huntington’s disease
- Huntington's disease (HD) is an autosomal-dominant, progressiveneurodegenerative
disorder with a distinct phenotype

Presentation
- Typically, onset of symptoms at middle age
- Early signs may be personality change, self-neglect and clumsiness
- Incoordination
- Cognitive decline
- Behavioural difficulties
- Later → Chorea, dystonia, rigidity and dementia

Q-14
A 7 year old male child is brought to the paediatrician’s office by his concerned
mothr. She states that he is unable to climb stairs and that he is being bullid in
school as he cannot run with his classmats on the playground. Upon
examination, it is noted tht he has diminished deep tendon reflexes and
hypertrophy of his calf muscles bilaterally. What is the SINGLE most likely
diagnosis?
 A. Duchenne muscular dystrophy
B. Guillain-Barre syndrome
C. Becker’s muscular dystrophy
D. Polymyositis
E. Motor neurone disease

ANSWER:
Duchenne muscular dystrophy

EXPLANATION:
Duchenne muscular dystrophy
X-linked recessive condition which presents in early childhood and inevitably
progresses. Some carriers also have symptoms. New mutations are common in DMD;
this means that female relatives of a child with DMD are not necessarily carriers of the
gene.

Presentation:
• Classic PLAB 1 presentation is a boy coming into the clinic by age 4-8 years
• Delayed motor milestone:
o walking at > 18 months, can’t hold objects
o Inability to run - waddling gait when attempting to do so.
• Gower’s sign, proximal muscle weakness +/- Respiratory or cardiac
signs/symptoms
• Elevated creatine kinase, AST, ALT

Diagnosis:
- Creatine kinase - initial → (CK levels are very high (10-100 x normal from birth).
- Blood sample and muscle biopsy → genetic testing for dystrophin mutations →PCR
- Genetic testing after a positive biopsy diagnosis of DMD is mandatory

Becker’s muscular dystrophy (BMD)

• is similar to the more common muscular dystrophy – Duchenne muscular dystrophy
(DMD) – but the clinical course is milder.
• As with DMD, there is muscle wasting and weakness which is mainly proximal.
• Generally, walking difficulties begin after the age of 16 in Becker’s muscular
dystrophy

Q-15
The parents of two children would like to try for another child. Their first child
was diagnosed with cystic fibrosis and their second child is healthy. Both the
parents are healthy. What is the chances of their next child being a carrier?

A. 1:4
B. 1:2
C. 2:3
D. 1:8
 E. 1:16

ANSWER:
1:2
EXPLANATION:
Pay special attention to the final line of the question. In this question they arespecifically
asking for chances that this boy is a carrier (not an affected child with cysticfibrosis). In
other stems and questions, they may ask for the chance that this boy willhave the
disease.

Both parents here would have to be carriers in order to produce a child with
cysticfibrosis as it is an autosomal recessive disease.

Therefore, the chances of having:

- An unaffected child is 1:4
- An unaffected ‘carrier’ child is 1:2
- An affected child is 1:4

Q-16
A 3 year old child has been diagnosed with Duchenne muscular dystrophy. His
mother is now pregnant with her second child who is also male. There is no
family history of the disease besides the 3 year old child who is affected. She
wishes to know the chances of her second child also being affected. What is the
likelihood of her second child having Duchenne muscular dystrophy?

A. 100%
B. 50%
C. 25%
D. 12.5%
 E. 0%
ANSWER:
50%
EXPLANATION:
Duchenne muscular dystrophy is a X-linked recessive disorder. Since the first child is
affected, it means that the mother is a carrier. Since the sex of the second child is
known and noted to be male, the chances of child being affected are 50%.

Other notable X-linked recessive disorders are

• Haemophilia A and B
• Red-green colorblindness

Q-17
A 15 year old girl presents to the GP surgery with primary amenorrhoea. She has
a short stature, low set of ears and a broad chest with widely spaced nipples.
Wht is the SINGLE most likely diagnosis?

A. Down’s syndrome
B. Klinefelter’s syndrome
C. Fragile X syndrome
D. Turner syndrome
E. Normal physiological findings

ANSWER:
Turner syndrome
EXPLANATION:
Primary amenorrhoea, short stature, low set of ears and a broad chest with widely
spaced nipples are features of Turner syndrome

Down’s syndrome and Fragile X syndrome do not present with primary amenorrhoea.

Klinefelter’s syndrome affects males.

This girl would likely need oestrogen replacement therapy to help development of her
secondary characteristics and help menstruate spontaneously.

Q-18
A 4 year old boy presents to clinic after an incidental finding of elevated creatine
kinase. The mother gives a history of the boy walking at 18 months and sluggish
when he runs, climbs stairs, rising from a sitting position, or riding his tricycle.
Compared to his older sister at the same age, he has difficulty holding onto small
objects. What is the SINGLE most likely diagnosis?

A. Duchenne muscular dystrophy

B. Becker’s muscular dystrophy
C. Myotonic muscular dystrophy
D. Spinal muscular atrophy type 1
E. Lambert-Eaton syndrome

ANSWER:
Duchenne muscular dystrophy

EXPLANATION:
This is a classic presentation of Duchenne muscular dystrophy. The stem would usually
present with a pre-school boy and a history of abnormal gait. Clues: “rising from a
sitting position” (Gower’s sign), hypertrophic calf muscles, and elevated creatine kinase.
The presentation of Becker’s has an onset of around 10 years old or presenting with a
young man who is unable to walk. Myotonic muscular dystrophy presents at birth with
multi-system complications as with spinal muscular atrophy type 1. With option E,
symptoms would be similar to Duchenne’s but the proximal muscle weakness would
improve with exercise and usually is associated with a tumour of the lung.

Q-19
A 28 year old lady with a family history of cystic fibrosis comes for genetic
counselling and wants the earliest possible diagnostic test for cystic fibrosis for
the baby she is planning. She is planning to get pregnant in the near future and
she is not in favor of termination. What is the SINGLE most appropriate test to
recommend?
 A. Chorionic villous sampling
B. Amniocentesis
C. Preimplantation genetic diagnosis
D. Chromosomal karyotyping
E. Non-invasive prenatal testing

ANSWER:
Pre-implantation genetic diagnosis

EXPLANATION:
This women is not yet pregnant but planning for pregnancy. The earliest
possiblediagnostic test for cystic fibrosis is a pre-implantation genetic diagnosis
(PGD).Preimplantation genetic diagnosis (PGD) is a procedure used prior to
implantation tohelp identify genetic defects within embryos created through in vitro
fertilization toprevent certain diseases or disorders from being passed on to the child.
The processhelps potential parents prevent the birth of a child with a serious genetic
condition.Specialist occasionally recommend these test if a woman has a family history
of aserious genetic condition (e.g. cystic fibrosis).

Q-20
A 7 year old male child presents with difficulty in climbing stairs. His parents
also note that he has difficulties when playing with his friends as he cannot keep
up with them. They describe a ‘waddling’ gait for their son when he attempts to
run and complains that he uses his hands to push himself up the stairs rather
than his feet. On examination, the tone and power in his lower legs are weakened
with absent reflexes and his calves are noted to have an increased diameter
bilaterally. What is the SINGLE most likely area for his defect?

A. Motor cortex
B. Pyramidal tract
C. Motor end plate
D. Striated muscle
E. Cerebellum

ANSWER:
Striated muscle

EXPLANATION:
This patient has Duchenne’s muscular dystrophy. This is an X-linked recessive
condition which means it only affects males. The mutation causes faulty coding of the
dystrophin protein which is found in muscle fibre membranes therefore, the correct
answer is that the lesion is located in the striated muscle.

Q-21
An 8 year old boy is clinically obese. As a baby he was floppy and difficult to
feed. He now has learning difficulties and is constantly eating despite measures
by his parents to hide food out of his reach. What is the SINGLE most likely
diagnosis?

A. Cushing’s syndrome
B. Congenital hypothyroidism
C. Prader Willi syndrome
D. Laurence Moon Biedl syndrome
E. Down’s syndrome

ANSWER:
Prader Willi syndrome

EXPLANATION:
Prader Willi syndrome rare congenital disorder characterized by learning
difficulties,growth abnormalities, and obsessive eating, caused mostly by deletion of the
paternallyinherited chromosomal 15q11.2-q13 region.

Prader-Willi syndrome (PWS)

• The striking feature of PWS is massive hyperphagia with associated compulsive
food-seeking, and consequent marked obesity.

Clinical features
• Neonates: hypotonia, sleepiness, unresponsiveness, narrow bifrontal diameter,
triangular mouth (feeding difficulties and swallowing problems), strabismus,
acromicria (shortness of extremities)
• Childhood/adolescence: short stature, hypogenitalism, behavioural disorders
(overeating and obesity, self-injurious behaviour).
• Associated features: Small hands and feet, cleft palate, almond-shaped eyes,
strabismus, clubfoot, scoliosis.

Q-22
A 59 year old man has shown a change in his mood and personality over a 9
monthperiod. He has subsequently developed difficulty with memory and
concentration, andthen progressive fidgety movements of his limbs and facial
musculature. By the time ofmedical assessment he has frank choreiform
movements and a mini-mental state examof 21/30. He was adopted and therefore
no information on his family history isavailable. He has 3 adult children (27, 30,
33) of whom the 2 youngest areasymptomatic. However, the oldest son has
recently been investigated by theneurology department for slightly erratic
behavior and fidgety restless movements ofboth legs. Based on the likely clinical
diagnosis, what is the SINGLE most likely mode ofinheritance?

A. Autosomal dominant inheritance with anticipation

B. Autosomal dominant with variable penetrance
C. Autosomal recessive
D. X-linked
E. Mitochondrial disorder
ANSWER:
Autosomal dominant inheritance with anticipation

EXPLANATION:
This patient is suffering from Huntington's disease. It is an autosomal dominantdisorder
with anticipation. The term “anticipation” is a phenomenon whereby as thegenetic
disorder is passed on to the next generation, the symptoms of the geneticdisorder
become apparent at an earlier age. This occurs in each generation wherebythe
symptoms would appear earlier and earlier.

Huntington’s disease
- Huntington's disease (HD) is an autosomal-dominant, progressiveneurodegenerative
disorder with a distinct phenotype

Presentation
- Typically, onset of symptoms at middle age
- Early signs may be personality change, self-neglect and clumsiness
- Incoordination
- Cognitive decline
- Behavioural difficulties
- Later → Chorea, dystonia, rigidity and dementia

Q-23
A 5 year old boy has recurrent chest infections and offensive stool. He is brought
by his mother to his GP surgery with concerns that he has another chest
infection. They seem to happen very year and sometimes twice a year. On
physical examination, he has coarse inspiratory crepitations. It is also noted that
he has finger clubbing. He is prescribed antibiotics for his chest infection. What
investigation(s) should be requested?

A. Endomysial antibody (IgA)

B. Sweat test
C. Heel prick test
D. Anti-gliadin antibody (IgA or IgG)
E. Random fasting glucose and HbA1c

ANSWER:
Sweat test

EXPLANATION:
This child has recurrent chest infections and malabsorption. Cystic fibrosis should be at
the top of the list of differentials. With established disease, finger clubbing is seen.
Sweat testing confirms the diagnosis of cystic fibrosis and is 98% sensitive.

A heel prick test (Guthrie’s test) is wehre a small sample of blood is taken from your
baby’s heel when the baby is 7 to 10 days old. This blood is sent to a lab where it is
tested for several conditions, one of which is cystic fibrosis. This cannot be used for a 5
year old child.

Q-24
A patient who presents with bilateral cerebellopontine tumours, bilateral
sensorineural hearing loss and café au lait spots is pregnant. What are the
chances of her child having the same condition?

A. 1:1
B. 1:2
C. 1:4
D. 3:4
E. 1:8

ANSWER:
1:2

EXPLANATION:
In order to work out probability of inheritance, you need to know the disease inquestion.
This woman has neurofibromatosis. Neurofibromatosis is an autosomaldominant
condition therefore the chances of this woman’s child having the condition is50% or 1:2.

Neurofibromatosis
NF is a genetic disorder causing lesions in the skin, nervous system and skeleton.
Theneurofibromatoses are autosomal dominant genetic disorders that encompass the
rarediseases NF1, NF2, and schwannomatosis

Type 1 is the more common form

Type 2 is a central form with CNS tumours rather than skin lesions:
Schwannomatosis is a recently recognized form of neurofibromatosis, characterized
bymultiple non-cutaneous schwannomas, which is a histologically benign nerve
sheathtumour:
UNAFFECTED AFFECTED PARENT (Mother)
PARENT (Father) H h
h Hh Hh
h Hh hh

Diagnostic criteria for NF1

The diagnostic criteria for NF1 require at least two of seven criteria:
1. At least six café-au-lait spots or hyperpigmented macules
2. Axillary or inguinal freckles.
3. Two or more typical neurofibromas or one plexiform neurofibroma.
4. Optic nerve glioma.
5. Two or more iris hamartomas. They are called Lisch nodules and are seen by slit-
lamp examination.
6. Sphenoid dysplasia or typical long-bone abnormalities such as arthrosis.
7. Having a first-degree relative with NF1.

Knowing that neurofibromatosis is an autosomal dominant condition is important for

PLAB, as is knowing the difference between NF1 and NF2.

Q-25
A 30 year old man and wife present to the reproductive endocrine clinic as they
have been trying to conceive for the last 3 years. They have intercourse 3 times a
week and do not use contraception. The man is tall and has bilateral
gynaecomastia. Examination of the testes reveals bilateral small, firm testes.
Which is the SINGLE best investigation that could lead to a diagnosis?

A. Computed tomography scan of the pituitary gland

B. Chromosomal analysis
C. Serum gonadotropin levels
D. Serum testosterone levels
E. Follicle-stimulating hormone (FSH) and luteinising hormone (LH) levels

ANSWER:
Chromosomal analysis

EXPLANATION:
Many with known Klinefelter's syndrome are not diagnosed until they are adults.
TheSINGLE best test that confirms diagnosis is a chromosomal analysis. In this
question,attending a reproductive endocrine clinic and trying to concieve for the last 3
years is ahint telling you about his infertility.

Klinefelter’s syndrome (XXY)

Findings
- Mental retardation (average IQ 85-90)
- Behavioral problems
- Long limbs ( decreased upper:lower segment ratio)
- Tall and slim
- Hypogonadism
- Infertility
- Gynecomastia

Q-26
A 13 year old girl is short for her age. She has extra folds of skin on the neck and
her mother suspects she has Turner syndrome . What is the SINGLE most likely
finding in Turner’s syndrome

A. Asplenism
B. Hydrocephalus
C. Ovarian failure
D. Epicanthal folds
 E. Polydactyly

ANSWER:
Ovarian failure

EXPLANATION:
The two most important clinical features of Turner’s syndrome that you must not forget
is impaired pubertal growth and ovarian failure.

Q-27
A 42 year old primiparous woman has a stillbirth at 32 weeks. The baby is noted
to have microcephaly, micrognathia, a prominent occiput and prominent
calcaneus. What is the SINGLE most likely genetic disorder?

A. Down syndrome
B. Fragile X syndrome
C. Edwards syndrome
D. DiGeorge syndrome
E. Patau syndrome

ANSWER:
Edwards syndrome

EXPLANATION:
The baby here has Edwards syndrome also known as trisomy 18. It is seen in rising
maternal age. The prominent calcaneus (also known as rocker bottom feet) is seen in
Edwards syndrome. Rocker bottom feet is also seen in Patau syndrome however with
the other signs such as microcephaly, micrognathia (small jaw) and a prominent
occiput, Edwards syndrome is the likely genetic disorder here.

Majority of Edward syndrome cases in the UK are picked up antenatally based on

screening by maternal age, serum markers and sonographic abnormalities such as
growh restriction, polyhydramnios, overlapping of fingers, congenital heart defects, and
omphalocele.

The most common sonographic markers detected in late first or early second trimester
are increased nuchal translucency thickness and absence or hypoplasia of the nasal
bone.

Half of these infants with Edward syndrome do not survive beyond the first week of life.
Majority of them do not survive longer than a year.