paediatric genetics

Question 1

what is the karyotype in Down’s syndrome

Answer 1

trisomy 21

Question 2

what other health conditions is Down’s syndrome associated with

Answer 2

• learning disability
• congenital heart disease
• hypothyroidism
• immune diseases
• early onset Alzheimer’s

Question 3

advances in testing for Down’s syndrome

Answer 3

non-invasive pre-natal testing

• using next generation sequencing of free fetal DNA in maternal blood

more of these pregnancies will be detected prenatally

Question 4

ethical issues re. prenatal testing for Down’s syndrome

Answer 4

• prenatal screening for DS is regarded as standard of care in western obstetrics
• non-invasive prenatal testing is no risk to fetus
• is a world w/o DS acceptable

Question 5

what are the 3 common trisomies

Answer 5

21

18

13

Question 6

what does congenital mean

Answer 6

present at birth

can be genetic/environmental cause or mixed

Question 7

causes of multiple congenital anomaly syndromes

Answer 7

30% single gene disorders

10% chromosomal

5% teratogens

55% unknown

Question 8

how common are congenital anomalies

Answer 8

3% of all births

20% children’s hospital admissions

30% of infant deaths

Question 9

how common are multiple congenital anomaly syndromes

Answer 9

individually rare

common as a group

Question 10

what is a syndrome

Answer 10

pattern of clinical features occurring together

a distinct group of symptoms and signs which, associated together, form a characteristic clinical picture or entity

cause may be known/unknown

Question 11

synthesis of information to determine cause of congenital syndrome

Answer 11

clinical experience

Gestalt (see a pattern and recognise it instantly) vs recognition of pattern of features

use of genetic databases

rapidly increasing utility of genomic analysis - revolutionising diagnosis

Question 12

diagnosing a rare intellectual disability +/- malformation syndrome

Answer 12

• hx
• description
• recognition of patterns
• testing
  
  • standard - biochemical, chromosome structure, microarray
  • targeted testing
  • gold standard but expensive: trio based exome/genome

Question 13

description of the dysmorphic child

Answer 13

• position and shape of facial features
• hands
• growth of child
• general features

Question 14

abnormalities of the eyes

Answer 14

• hypertelorism: eyes are too distant from each other
  
  • inner canthal distance (ICD) and inter-pupillary distance (IPD) increased
• telecanthus/epicanthic folds - ICD increased but IPD normal?

Question 15

hand measurements and what conditions might they be relevant in

Answer 15

• finger length
• digital abnormalities
• palmar creases

Down’s syndrome, Marfan syndrome

Question 16

hand measurements in marfan’s syndrome

Answer 16

middle finger/total hand length is usually >44%

indicates long fingers

Question 17

finger descriptions

Answer 17

arachnodactyly - long thin fingers

brachydactyly - short fat fingers

Question 18

head measurements and description

Answer 18

shape

size: macrocephaly, microcephaly

ear position: low set, posteriorly rotated indicates lack of maturity

Question 19

when do malformations occur

Answer 19

alone or as part of a syndrome

• e.g. polysyndactyly alone - Hox D13 (one cause)
• acrocephalopolysyndatyly (Greig/GLI3)

Question 20

what is polysyndactyly

Answer 20

fingers stuck together

Question 21

acrocephalopolysyndatyly

Answer 21

too many fingers with some stuck together

Question 22

features of Greig syndrome

Answer 22

tall forehead

polydactyly

syndactyly

Question 23

describe sequence

Answer 23

• one abnormality leads to another, can have multiple causes
• e.g. Pierre Robine sequence - small chin to cleft palate
• fetal akinesia sequence - reduced fetal movement, reduced breathing, contractures, clefting, lung hypoplasia

Question 24

how does a small chin lead to cleft palate in Pierre Robin sequence

Answer 24

small chin

not enough room in the mouth

tongue presses on the roof of the mouth

pushes against the palate and results in cleft palate

Question 25

causes of fetal akineasia

Answer 25

muscular

neurological

reduction in fluid

Question 26

features of fetal akinesia on 20wk scan

Answer 26

abnormal limb position

reduced fetal movements

mild polyhydramnios

Question 27

what is deformation and disruption

Answer 27

pattern of development is normal to begin with but then becomes abnormal

• defortmation: organ parts are there
• disruption: parts of organ/body part absent

e.g. amniotic fluid bands

Question 28

what is association

Answer 28

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

mechanism is unclear

Question 29

example of association

Answer 29

VATER

• vertebral anomalies
• ano-rectal atresia
• tracheo-oesophageal fistula
• radial anomalies

Question 30

chromosomal abnormality in Turner syndrome

Answer 30

45X

X chromosome but no Y

Question 31

features of turner syndrome

Answer 31

• lymphoedema - puffy feet, nuchal translucency, cystic hygroma
• increased carrying angle, low hairline, wide spaced nipples, sandal gap (between big toe and 2nd toe)
• short stature, occasionally mild learning difficulty
• coarctation of aorta, hypothyroidism, UTI, osteoporosis, HT
• 1y amenorrhoea, infertility
• hormonal therapy mitigates some features

Question 32

genetic investigation of learning disability

Answer 32

microarray

fragile X

targeted tests driven by phenotype

trio based exome vs trio based genome analysis - funding issues

Question 33

features of 22q11 deletion

Answer 33

CATCH 22

cleft palate

abnormal facies

thymic hypoplasia/immune deficiency of T cells

calcium abnormalities

heart problems

Question 34

importance of phenotyping

Answer 34

• phenotype is key to assessment of clinical relevance
• accurate description of clinical features is important
• diagnosis can help with future planning, future pregnancies, clinical care and treatment