Genetics

Question 2

What is Down’s Syndrome

Answer 2

Down’s Syndrome is caused by three copies of chromosome 21. It is also called trisomy 21. It gives characteristic dysmorphic features and is associated with a number of associated conditions. Th

Question 3

Down’s Syndrome

Dysmorphic Features

Answer 3

• Hypotonia (reduced muscle tone)
• Brachycephaly (small head with a flat back)
• Short neck
• Short stature
• Flattened face and nose
• Prominent epicanthic folds
• Upward sloping palpebral fissures
• Single palmar crease

Question 4

What are Epicanthic folds and palpebral fissures

Answer 4

Epicanthic folds are folds of skin covering the medial portion of the eye and eyelid. The palpebral fissures are the gaps between the lower and upper eyelid.

Question 5

Complications of Down syndrome

Answer 5

• Learning disability
• Recurrent otitis media
• Deafness. Eustachian tube abnormalities lead to glue ear and conductive hearing loss.
• Visual problems such myopia, strabismus and cataracts
• Hypothyroidism occurs in 10 – 20%
• Cardiac defects affect 1 in 3, particularly ASD, VSD, patent ductus arteriosus and tetralogy of Fallot
• Atlantoaxial instability

Question 6

What are Antenatal Screening for Down’s Syndrome

Answer 6

Combined Test

Triple Test

Quadruple Test

Question 7

What is Combined Test

Answer 7

The combined test is the first line, most accurate and test of choice where possible. This test is performed between 11 and 14 weeks gestation. It involves combining results from ultrasound and maternal blood tests.

Ultrasound measures nuchal translucency, which is the thickness of the back of the neck of the fetus. Down’s syndrome is one cause of a nuchal thickness over 6mm.

Maternal blood tests:

• Beta‑human chorionic gonadotrophin (beta-HCG). A higher result indicates a greater risk.
• Pregnancy‑associated plasma protein‑A (PAPPA). A lower result indicates a greater risk.

Question 8

What is Triple Test

Answer 8

The triple test is performed between 14 and 20 weeks gestation. It only involves maternal blood test results:

• Beta-HCG. A higher result indicates greater risk.
• Alpha-fetoprotein (AFP). A lower result indicates a greater risk.
• Serum oestriol (female sex hormone). A lower result indicates a greater risk.

Question 9

What is Quadruple Test

Answer 9

The quadruple test is performed between 14 and 20 weeks gestation. It is identical to the triple test but also includes maternal blood for inhibin-A. A higher inhibin-A indicates a greater risk

Question 10

The screening tests provide a risk score for the fetus having Down’s syndrome. When the risk of Down’s is greater than 1 in 150 (this result occurs in around 5% of tested women) the woman is offered________ or ______ _______ ______

Answer 10

The screening tests provide a risk score for the fetus having Down’s syndrome. When the risk of Down’s is greater than 1 in 150 (this result occurs in around 5% of tested women) the woman is offered amniocentesis or chorionic villus sampling.

Question 11

WHat is Chorionic villus sampling (CVS) and Amniocentesis

Answer 11

• Chorionic villus sampling (CVS) involves an ultrasound guided biopsy of the placental tissue. This is used when testing is done earlier in pregnancy (before 15 weeks).
• Amniocentesis involves ultrasound guided aspiration of some amniotic fluid using a needle and syringe. This is later in pregnancy once there is enough amniotic fluid to make it safer to take a sample.

Question 12

What is Non-Invasive Prenatal Testing

Answer 12

Non-invasive prenatal testing (NIPT) is a relatively new test for detecting abnormalities in the fetus during pregnancy. It involves a simple blood test from the mother. The blood will contain fragments of DNA, some of which will come from the placental tissue and represent the fetal DNA. These fragments can be analysed and detect conditions such as Down’s.

Question 13

Management for down syndrome

Answer 13

Management involves supportive care from the multidisciplinary team to help them meet their needs:

• Occupational therapy
• Speech and language therapy
• Physiotherapy
• Dietician
• Paediatrician
• GP
• Health visitors
• Cardiologist for congenital heart disease
• ENT specialist for ear problems
• Audiologist for hearing aids
• Optician for glasses
• Social services for social care and benefits
• Additional support with educational needs
• Charities such as the Down’s Syndrome Association

Question 14

TOM TIP: When asked by an examiner about the management of a complex multi system disorder such as Down’s syndrome, always start your answer with

Answer 14

“management would involve members of the multidisciplinary team”

Question 15

What is Klinefelter syndrome

Answer 15

Klinefelter syndrome occurs when a male has an additional X chromosome, making them 47 XXY. Under normal circumstances males have XY sex chromosomes and females have XX sex chromosomes.

Rarely people with Klinefelter syndrome can have even more X chromosomes, such as 48 XXXY or 49 XXXXY. This is associated with more severe features.

Question 16

Features of Klinefelter syndrome

Answer 16

Usually patients with Kleinfelter syndrome appear as normal males until puberty. At puberty can develop features suggestive of the condition:

• Taller height
• Wider hips
• Gynaecomastia
• Weaker muscles
• Small testicles
• Reduced libido
• Shyness
• Infertility
• Subtle learning difficulties (particularly affecting speech and language)

Question 17

There is no way to treat the underlying genetic cause of Klinefelter syndrome. Treatment aims to help with the features of the condition:

Answer 17

• Testosterone injections improve many of the symptoms
• Advanced IVF techniques have the potential to allow fertility
• Breast reduction surgery for cosmetic purposes

Multidisciplinary team input:

• Speech and language therapy to improve speech and language
• Occupational therapy to assist in day to day tasks
• Physiotherapy to strengthen muscles and joints
• Educational support where required for dyslexia and other learning difficulties

Question 18

Klinefelter Syndrome

There is a slight increased risk of what diseases:

Answer 18

Breast cancer compared with other males (but still less than females)

Osteoporosis

Diabetes

Anxiety and depression

Question 19

What is turners syndrome

Answer 19

Turner syndrome occurs when a female has a single X chromosome, making them 45 XO. The O referrs to an empty space where the other X chromosome should be. Life expectancy is close to normal.

Question 20

Features of turners syndrome

Answer 20

• Short stature
• Webbed neck
• High arching palate
• Downward sloping eyes with ptosis
• Broad chest with widely spaced nipples
• Cubitus valgus
• Underdeveloped ovaries with reduced function
• Late or incomplete puberty
• Most women are infertile

Question 21

What is Cubitus valgus

Answer 21

Cubitus valgus refers to an abnormal feature of the elbow. When the arm is extended downwards with the palms facing forward, the angle of the forearm at the elbow is exaggerated, angled away from the body.

Question 22

Turners syndrome

P: The three classic features to remember and look out for in exams are

Answer 22

short stature, webbed neck and widely spaced nipples.

Question 23

Turners Syndrome

Associated Conditions

Answer 23

• Recurrent otitis media
• Recurrent urinary tract infections
• Coarctation of the aorta
• Hypothyroidism
• Hypertension
• Obesity
• Diabetes
• Osteoporosis
• Various specific learning disabilities

Question 24

Management of Turners Syndrome

Answer 24

There is no way to treat the underlying genetic cause of Turner syndrome. Treatment aims to help with the symptoms of the condition:

• Growth hormone therapy can be used to prevent short stature
• Oestrogen and progesterone replacement can help establish female secondary sex characteristics, regulate the menstrual cycle and prevent osteoporosis
• Fertility treatment can increase the chances of becoming pregnant

Patients need monitoring for the associated conditions and complications. Treatable conditions such as hypertension and hypothyroidism should be managed appropriate.

Question 25

What is noonan syndrome

Answer 25

Noonan syndrome is a genetic condition. There are a number of different genes that cause Noonan syndrome. The majority for cases are inherited in an **autosomal dominan**t way. There is variation in the signs and symptoms of Noonan syndrome, depending on the underlying cause

Question 26

Features of Noonan Syndrome

Answer 26

* Short stature * Broad forehead * Downward sloping eyes with ptosis * **Hypertelorism (wide space between the eyes)** * Prominent nasolabial folds * Low set ears * Webbed neck * Widely spaced nipples

Question 27

Associated Conditions with Noonan syndrome

Answer 27

* **Congenital heart disease**, particularly pulmonary valve stenosis, hypertrophic cardiomyopathy and ASD * **Cryptorchidism** (undescended testes) can lead to infertility. Fertility is normal in women. * **Learning disability** * **Bleeding disorders** * **Lymphoedema** * Increased risk of leukaemia and neuroblastoma

Question 28

Noonan syndrome management Commplications?

Answer 28

There is no treatment for the underlying genetic defect. Management is supportive with involvement of the multidisciplinary team. The main complication is congenital heart disease and often patients will require corrective heart surgery.

Question 29

What is Marfan syndrome

Answer 29

Marfan syndrome is an **autosomal dominant** condition affecting the gene responsible for creating **fibrillin.** Fibrillin is an important component of connective tissue. This means people with Marfan syndrome have features resulting from **abnormal connective tissue.**

Question 30

Features of Marfans Syndrome

Answer 30

* Tall stature * Long neck * Long limbs * Long fingers (arachnodactyly) * High arch palate * Hypermobility * Pectus carinatum or pectus excavatum * Downward sloping palpable fissure

Question 31

If you meet a patient in your OSCE that appears tall, has hypermobility or a murmur suggestive of mitral or aortic regurgitation, think of

Answer 31

Marfan syndrome

Question 32

Associated Conditions of Marfans

Answer 32

* Lens dislocation in the eye * Joint dislocations and pain due to hypermobility * Scoliosis of the spine * Pneumothorax * Gastro-oesophageal reflux * Mitral valve prolapse (with regurgitation) * Aortic valve prolapse (with regurgitation) * Aortic aneurysms

Question 33

Management of Marfans

Answer 33

The greatest risk is from the associated cardiac complications, particularly valve prolapse and aortic aneurysms. Where these complications occur they may require **surgical correction.** The aim of management is to minimise the blood pressure and heart rate to minimise the stress on the heart and the risk of complications developing. This is achieved by lifestyle changes, such as avoiding intense exercise and avoiding caffeine and other stimulants. **Preventative medications such as beta blockers and angiotensin II receptor antagonists** can also help reduce the risk of complications. Pregnancy has to be carefully considered, as it carries a significant risk of developing **aortic aneurysms and associated complications.** **Physiotherapy** can be helpful in strengthening joints and reducing symptoms arising from hypermobility. **Genetic counselling** is important in considering the implications of having children that may be affected by the condition. Patients are also regularly followed up and monitored for complications. This often involves yearly **echocardiograms and review by an ophthalmologist.**

Question 34

What is Fragile X syndrome

Answer 34

Fragile X syndrome is caused by a mutation in the **FMR1 (fragile X mental retardation 1)** gene on the X chromosome. The FMR1 gene codes for the **fragile X mental retardation protein,** which plays a role in cognitive development in the brain. It is **X-linked**, but it is unclear whether it is **dominant or recessive.** Males are always affected, but females can vary in how much they are affected. This is because females have a spare normal copy of the FMR1 gene on their other X chromosome. When the mother is phenotypically normal, the affected child may have inherited the X chromosome from their mother, or it may result from a **de novo** (random) mutation.

Question 35

Features Fragile X syndrome

Answer 35

* Intellectual disability * Long, narrow face * Large ears * Large testicles after puberty * Hypermobile joints (particularly in the hands) * Attention deficit hyperactivity disorder (ADHD) * Autism * Seizures

Question 36

Management of fragile X syndrome

Answer 36

There is no cure for the condition. Management is supportive and involves treating the symptoms. This involves the multidisciplinary team to support the learning disability, manage autism and ADHD and treat seizures if they occur. Life expectancy is similar to the general population depending on associated disabilities and complications

Question 37

What is Prader-Willi Syndrome

Answer 37

Prader-Willi Syndrome is a genetic condition caused by the loss of functional genes on the **proximal arm** of the **chromosome 15** inherited from the father. This can be due to a **deletion** of this portion of the chromosome, or when both copies of chromosome 15 are inherited from the mother.

Question 38

Prader-Willi Syndrome Features

Answer 38

* Constant insatiable hunger that leads to obesity * Poor muscle tone as an infant (hypotonia) * Mild-moderate learning disability * Hypogonadism * Fairer, soft skin that is prone to bruising * Mental health problems, particularly anxiety * Dysmorphic features * Narrow forehead * Almond shaped eyes * Strabismus * Thin upper lip * Downturned mouth

Question 39

The key feature everyone remembers for Prader-Willi syndrome is

Answer 39

the insatiable hunger.

Question 40

There is no cure for prader-Willi Syndrome Supportive care from the multidisciplinary team to manage features:

Answer 40

* Dieticians play a very important role * Education support * Social workers * Psychologists or psychiatrists * Physiotherapists * Occupational therapists

Question 41

What is Angelman syndrome

Answer 41

is a genetic condition caused by loss of function of the **UBE3A gene**, specifically the copy of the gene that is inherited from the mother. This can be caused by a deletion on chromosome 15, a specific mutation in this gene or where two copies of **chromosome 15** are contributed by the father, with no copy from the mother

Question 42

Angelman Syndrome Features

Answer 42

* Delayed development and learning disability * Severe delay or absence of speech development * Coordination and balance problems (ataxia) * **Fascination with water** * **Happy demeanour** * Inappropriate laughter * Hand flapping * Abnormal sleep patterns * Epilepsy * Attention-deficit hyperactivity disorder * Dysmorphic features * Microcephaly * Fair skin, light hair and blue eyes * Wide mouth with widely spaced teeth TOM TIP: The novel features to remember and link with Angelman syndrome so you can spot it in your exams is the unusual fascination with **water, happy demeanour and widely spaced teeth.**

Question 43

What is William Syndrome

Answer 43

William syndrome is caused by a **deletion** of genetic material on one copy of **chromosome 7,** resulting in the person only having a single copy of the genes on this deleted region (on the other chromosome 7). It usually the result of a **random deletion** around conception, rather than being inherited from an affected parent.

Question 44

William Syndrome Features

Answer 44

* Broad forehead * **Starburst eyes** (a star-like pattern on the iris) * Flattened nasal bridge * Long philtrum * Wide mouth with widely spaced teeth * Small chin * Very sociable trusting personality * Mild learning disability The distinctive features to remember with William syndrome are the **very sociable personality, the starburst eyes and the wide mouth with a big smile**. It is worth remembering the association with **supravalvular aortic stenosis and hypercalcaemia**, as these are unique features that are easy to test in exams.

Question 45

Associated Conditions with williams syndrome

Answer 45

* **Supravalvular aortic stenosis (narrowing just above the aortic valve)** * Attention-deficit hyperactivity disorder * Hypertension * **Hypercalcaemia**

Question 46

Management of Williams Syndrome

Answer 46

Like many other genetic syndromes, there is no cure and management focuses on a multi-disciplinary team approach to managing individual problems and supporting the patient and family. Echocardiograms and blood pressure monitoring are important to assess for aortic stenosis and hypertension. **A low calcium diet** may be required to control hypercalcaemia, and they should avoid calcium and vitamin D supplements.