Paediatric Genetics

Question 1

Down syndrome - Trisomy 21

what problems/features are seen in downs syndrome?

Answer 1

• Learning disability
• Congenital heart disease
• Hypothyroidism
• Immunity (immune issues)
• Early onset Alzheimer disease

Question 2

what does non-invasive prenatal testing mean for down syndrome pregnancies?

Answer 2

•Non-invasive prenatal testing will mean more of these pregnancies are detected prenatally (look at free foetal DNA in mothers blood)

Question 3

What are the Ethics issue around prenatal screening for downs syndrome?

Answer 3

• Prenatal screening for Down syndrome is regarded as standard of care in Western obstetrics
• Non-invasive prenatal testing using next-generation sequencing of free fetal DNA in maternal blood is no risk to fetus
• Is a world without Down syndrome acceptable?

Question 4

what is congenital

Answer 4

• present at birth
• genetic or environmental
• or both

Question 5

what are Multiple Congenital Anomaly Syndromes?

Answer 5

Multiple congenital anomalies (MCAs) are defined as two or more unrelated major structural malformations that cannot be explained by an underlying syndrome or sequence

Question 6

what causes Multiple Congenital Anomaly Syndromes?

Answer 6

• single gene disorders 30%
• 10% chromosomal
• 5% teratogens
• 55% unknown

Question 7

how common do Congenital Anomalies cause problems?

Answer 7

• 3% all births
• 20% children’s hospital admissions
• 30% infant deaths

Question 8

how common are Multiple Congenital Anomaly Syndromes?

Answer 8

• individually rare
• (all syndromes together) common as a group
• Syndrome = pattern of clinical features occurring together

Question 9

How to diagnose a rare intellectual disability + / or malformation syndrome?

Answer 9

• History
• Description (of what we see)
• Recognition of patterns
• Testing
• Standard - biochemical, chromosome structure - Microarray now standard
• Targetted testing
• Moving to trio-based exome/genome

Question 10

How would Description of the Dysmorphic Child be done?

Answer 10

• Position and shape of facial features
• Hands
• Growth of child
• General features

Question 11

Description of the Dysmorphic Child - what things may you notice about a head?

Answer 11

• Shape
• Size: macrocephaly, microcephaly
• Ear position - Low set, posteriorly rotated indicates lack of maturity

Question 12

What dys morphic features may be present around the eyes?

Answer 12

• Hypertelorism (eyes spaced apart) - Inner canthal distance ICD and inter-pupillary distance IPD increased
• Telecanthus / epicanthic folds (fold of skin on inside of eye) - ICD and IPD increased

Question 13

what Hand measurements would you take?

Answer 13

• Finger length
• Digital abnormalities
• Palmar creases
• Examples Marfan syndrome (long thin fingers), Down syndrome (1 palmar crease)

Question 14

Finger descriptions:

• Arachnodactyly
• Brachydactyly

what do these terms mean?

Answer 14

• Arachnodactyly - the fingers and toes are abnormally long and slender, in comparison to the palm of the hand and arch of the foot. Also, the individual’s thumbs tend to be pulled inwards towards the palm
• Brachydactyly - a shortening of the fingers (can be fat) and toes due to unusually short bones. This is an inherited condition, and in most cases does not present any problems for the person who has it

Question 15

when can Malformationoccur and what is an example?

Answer 15

• alone or as part of a syndrome
• eg. polysyndactylty alone (Hox D13 one cause) – extra fingers with some stuck together
• or acrocephalopolysyndatyly (Greig / GLI3) – tall forehead, too many fingers and some stuck together

Question 16

Malformation: Polysyndactyly - what is it?

Answer 16

extra finger/toe with fusing

Polydactyly is the presence of extra fingers or toes, and syndactyly is the fusing together or webbing of two or more fingers or toes

Question 17

what is Acrocephalopolysyndactyly?

Answer 17

• Tall forehead
• Polydactyly
• Syndactyly

Question 18

Sequence - one abnormality leads to another, can have multiple causes

what are some examples?

Answer 18

•Pierre-Robin sequence

• small chin to cleft palate

•Fetal akinesia sequence

• reduced fetal movement
• reduced breathing
• contractures
• clefting
• lung hypoplasia

Question 19

Deformation & Disruption - what is it?

Answer 19

• Pattern of development normal to start with but becomes abnormal
• Deformation: Organ parts are there
• Disruption: Parts of organ / body part absent
• E.g. Amniotic bands

Deformation in terms of these fingers

Disruption in terms of finger not being present

Question 20

Association:

• two features or more features occur together more often than expected by chance
• mechanism unclear

what is VATER?

Answer 20

• V vertebral / VSD
• A anorectal atresia
• T tracheo-
• E (o)esophageal fistula
• R radial anomalies

Question 21

what is a Syndrome?

Answer 21

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

Cause may or may not be known

Question 22

what syndrome is shown here?

Answer 22

Turners is when you have an X chromosome but no Y – 45X

Question 23

what are the features of Turner syndrome 45,X?

Answer 23

• Lymphoedema (Puffy feet, nuchal translucency / cystic hygroma)
• Increased carrying angle, low hairline, wide sp nipples, sandal gap
• Short stature, occ. v mild learning diffy
• Coarctation of aorta, hypothyroidism, UTI, osteoporosis & hypertension
• Primary amenorrhoea & infertility
• Hormonal therapy mitigates some features

Question 24

Genetic investigation of learning disability 2021 - how is it done?

Answer 24

• Microarray (look at chromosome number)
• Fragile X (look at this gene if learning disability syndrome)
• Targetted tests driven by phenotype
• Trio based Exome vs. trio-base genome analysis
• Funding remains an issue
• Trio-based exome in Scotland and genome in England! (not much difference but for funding reasons we use exome in Scotland)

Question 25

22q11 deletion - what problems does it cause? Can see a resemblance Almond shaped eyes Simple ear Broad base nose with bulbus tip

Answer 25

* Cleft palate * Abnormal facies * Thymic hypoplasia / immune deficiency * Calcium * Heart problems - Caused by 22 deletion - “CATCH 22”

Question 26

There are patterns that are recognisable that doctors can be trained to notice to make a \_\_\_\_\_\_\_

Answer 26

diagnosis

Question 27

what are copy number variants?

Answer 27

A copy number variation (CNV) is when the number of copies of a particular gene varies from one individual to the next ## Footnote CNVs (copy number variants) are v common

Question 28

And sequence variation is \_\_\_\_\_\_

Answer 28

normal

Question 29

So how can we test thousands of genes and find the cause of the intellectual disability?

Answer 29

Question 30

what is the Importance of phenotyping?

Answer 30

* The key to assessment of clinical relevance is the phenotype * That’s why accurate description of clinical features is important * A diagnosis helps the family see the future * And can help with future pregnancy planning, clinical care and treatment