Paediatric Genetics Flashcards
Down syndrome - Trisomy 21
what problems/features are seen in downs syndrome?
- Learning disability
- Congenital heart disease
- Hypothyroidism
- Immunity (immune issues)
- Early onset Alzheimer disease
what does non-invasive prenatal testing mean for down syndrome pregnancies?
•Non-invasive prenatal testing will mean more of these pregnancies are detected prenatally (look at free foetal DNA in mothers blood)
What are the Ethics issue around prenatal screening for downs syndrome?
- 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?
what is congenital
- present at birth
- genetic or environmental
- or both
what are Multiple Congenital Anomaly Syndromes?
Multiple congenital anomalies (MCAs) are defined as two or more unrelated major structural malformations that cannot be explained by an underlying syndrome or sequence
what causes Multiple Congenital Anomaly Syndromes?
- single gene disorders 30%
- 10% chromosomal
- 5% teratogens
- 55% unknown
how common do Congenital Anomalies cause problems?
- 3% all births
- 20% children’s hospital admissions
- 30% infant deaths
how common are Multiple Congenital Anomaly Syndromes?
- individually rare
- (all syndromes together) common as a group
- Syndrome = pattern of clinical features occurring together
How to diagnose a rare intellectual disability + / or malformation syndrome?
- 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
How would Description of the Dysmorphic Child be done?
- Position and shape of facial features
- Hands
- Growth of child
- General features
Description of the Dysmorphic Child - what things may you notice about a head?
- Shape
- Size: macrocephaly, microcephaly
- Ear position - Low set, posteriorly rotated indicates lack of maturity
What dys morphic features may be present around the eyes?
- 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
what Hand measurements would you take?
- Finger length
- Digital abnormalities
- Palmar creases
- Examples Marfan syndrome (long thin fingers), Down syndrome (1 palmar crease)
Finger descriptions:
- Arachnodactyly
- Brachydactyly
what do these terms mean?
- 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
when can Malformationoccur and what is an example?
- 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
Malformation: Polysyndactyly - what is it?
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
what is Acrocephalopolysyndactyly?
- Tall forehead
- Polydactyly
- Syndactyly
Sequence - one abnormality leads to another, can have multiple causes
what are some examples?
•Pierre-Robin sequence
- small chin to cleft palate
•Fetal akinesia sequence
- reduced fetal movement
- reduced breathing
- contractures
- clefting
- lung hypoplasia
Deformation & Disruption - what is it?
- 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
Association:
- two features or more features occur together more often than expected by chance
- mechanism unclear
what is VATER?
- V vertebral / VSD
- A anorectal atresia
- T tracheo-
- E (o)esophageal fistula
- R radial anomalies
what is a Syndrome?
A distinct group of symptoms & signs which, associated together, form a characteristic clinical picture or entity
Cause may or may not be known
what syndrome is shown here?
Turners is when you have an X chromosome but no Y – 45X
what are the features of Turner syndrome 45,X?
- 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
Genetic investigation of learning disability 2021 - how is it done?
- 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)
22q11 deletion - what problems does it cause?
Can see a resemblance
Almond shaped eyes
Simple ear
Broad base nose with bulbus tip
- Cleft palate
- Abnormal facies
- Thymic hypoplasia / immune deficiency
- Calcium
- Heart problems
- Caused by 22 deletion
- “CATCH 22”
There are patterns that are recognisable that doctors can be trained to notice to make a _______
diagnosis
what are copy number variants?
A copy number variation (CNV) is when the number of copies of a particular gene varies from one individual to the next
CNVs (copy number variants) are v common
And sequence variation is ______
normal
So how can we test thousands of genes and find the cause of the intellectual disability?
what is the Importance of phenotyping?
- 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
