Paediatric genetics 1

Question 1

What genetic abnormality causes Down syndrome?

What problem in meiosis typically causes this abnormality to occur?

Answer 1

Trisomy of Chromosome 21

Caused by nondisjunction

Question 2

What are the main features of Down syndrome

Answer 2

Learning disabilities

Congenital heart disease

GI defects

Hypothyroidism

Immunity

Early onset alzhiemers

Question 3

What features on examination would you see in a patient with down’s syndrome?

Answer 3

Head - specific facies, brushfield spots in iris, epicanthic folds etc

Single palmar crease

Sandal gap - between 1st & 2nd toe

Hypotonia

Question 4

What congenital cardiac defects are seen in Down’s syndrome?

Answer 4

ECD (endocardial cushion defect) - most common

VSD (ventricular septal defect)

ASD (atrial septal defect)

There are others, and patients may have multiple at once - but these are the most common

Question 5

What GI conditions are seen in patients with down’s syndrome?

Answer 5

Duodenal atresia

Hirschsprung’s disease

Question 6

What are some complications are often seen in patients with Down’s syndrome?

Answer 6

Subfertility

Respiratory tract infections (due to impaired immunity)

EO Alzheimers

Hypothyroidism

Question 7

Aside from trisomy 21 (DS) - What other trisomies can occur?

Answer 7

Patau’s syndrome - trisomy 13

Edward’s syndrome - trisomy 18

Question 8

What are multiple congenital anomaly syndromes?

Answer 8

Multiple congenital anomaly syndromes (MCAs)

two or more unrelated major structural malformations that cannot be explained by an underlying syndrome or sequence

Many have similar patterns of clinical features occuring together - despite the variety of different genetic abnormalities causing them

Question 9

What types of genetic aborations can cause Multiple congenital anomalies?

Answer 9

Unknown - 55% of the time

Single gene disorders - 30%

Chromosomal - 10%

Teratogens - 5%

Question 10

Describe the clinical approach to a rare intellectual disabilities or malformations - as seen in MCAs

Answer 10

History & examination

Recognise patterns

Testing:

• biochemical
• microarray - to test chromosomal number & structure
• targeted testing
• trio based exome sequencing*

Question 11

In testing for MCAs - when would you do trio-based exome/genome sequencing?

Answer 11

If the prior testing (microarrays & targetted testing) havent identified any patterns

Question 12

When describing a dysmorphic child - what physical features should be examined?

Answer 12

Position & shape of facial features

Hands

Growth

General features

+ many more

Question 13

What aspects of the head should be inspected when examining a dysmorphic (MCA) child?

Answer 13

Shape (plagiocephaly etc)

Size (micro/macrocephaly)

Ear position (low set, small = lack of maturity)

Eyes

Question 14

What features of the eyes should would you look for in a child with MCAs?

Define each sign

Answer 14

Hypertolerism

Telecanthus & Epicanthal folds

Hypertelorism - genuine increased distance between eyes

Telecanthus - increased distance between medial canthi

Epicanthal folds - skin fold covering medial canthi

Question 15

ICD & IPD are useful measurements when looking for hypertelorism & telecanthus

What are these measurements and how do they compare?

Answer 15

ICD - inter canthal distance

IPD - inter pupillary distance

Hypertelorism - both ICD & IPD are increased as the entire eyes are displaced outwards

Telecanthus - IPD is normal, but ICD is increased

Question 16

What aspects of the hands do you inspect in assessing a dysmorphic child

Answer 16

Finger length

Finger abnormalities

Palmar creases

Question 17

Give example of finger abnormalities that you would look for in a dysmorphic child

Answer 17

arachnodactyly (long thin) - Marfan’s

brachydactyly (short fat)

polydactyly (extra fingers)

polysyndactyly (extra fingers & stuck together)

Question 18

What mutation causes polysyndactyly (BY ITSELF)?

Answer 18

HOX D13

Question 19

What is Greig syndrome?

What causes it?

What are its features?

Answer 19

Greig syndrome

Autosomal dominant dysmorphic syndrome caused by mutations of GLI3 gene

Features:

• acrocephalopolysyndactyly
• +/- macrocephaly
• +/- hypertelorism

Question 20

What is acrocephalopolysyndactyly?

Answer 20

Group of malformations seen in Greig syndrome

1) polysyndactyly = extra fingers with some stuck together
2) acrocephaly = tall forehead

Question 21

What malformation is characterised by congenital severe downwards & inwards deviation of the feet?

Answer 21

Congenital talipes equinovarus (CTEV)

(aka Clubfoot)

Can be a malformation by itself - or a feature of a syndrome (particularly some neurological syndromes)

Question 22

What is meant by ‘sequences’ of malformations?

Answer 22

one abnormality leads to another, can have multiple causes

Question 23

What are the features of the following sequences:

a) Pierre-robin sequence
b) fetal akinesia sequence

Answer 23

a) Pierre-Robin sequence:

1. small chin (which leads to)
2. cleft pallate

b) Fetal akinesia sequence:
* reduced fetal movement
* reduced breathing
* contractures
* clefting
* lung hypoplasia

Question 24

What do the terms deformation and disruption mean?

Answer 24

Patterns of development that are normal to start with but become abnormal

Deformation - organ parts are there - but deformed

Disruption - organs/parts of organs are missing (eg amniotic bands)

Question 25

What is meant by ‘association’?

What is the most common association - and its features?

Answer 25

two or more features occur together more often than expected by chance

Most common = VATER association

Question 26

What are the abnormalities seen in the VATER association?

Answer 26

VATER:

• V - vertebral body anomalies
• A - ano-rectal atresia
• T - tracheo-oEsophageal fistula
• R - radial anomalies