Paediatric Genetics Flashcards
What are the features of Down syndrome?
Trisomy 21 Learning disability Congenital heart disease Hypothyroidism Immunity (possibility of lymphopenia) Early onset Alzheimer disease
What form of Down’s testing poses no harm to the foetus?
Non-invasive prenatal testing using next-generation sequencing of free fetal DNA in maternal blood
What other trisomies are there?
13 and 18
What does congenital mean?
Present at birth
Can be caused by genetics, environment or both
What are Multiple Congenital Anomaly Syndromes?
Two or more unrelated major structural malformations that cannot be explained by an underlying syndrome or sequence
Single gene disorders 30%
10% chromosomal
5% teratogens
55% unknown
How common are congenital abnormalities?
3% all births
20% children’s hospital admissions
30% infant deaths
What is a syndrome?
Pattern of clinical features occurring together
Cause may or may not be known
How common are Multiple Congenital Anomaly Syndromes?
Individually rare
Common as a group
What are the principles of diagnosing syndromes?
Clinical experience
Gestalt vs. recognition of pattern of features
Use of databases
-22 000 genes - how many genetic disorders?
Rapidly increasing utility of genomic analysis is revolutionizing diagnosis
How is a rare intellectual disability and/or malformation syndrome diagnosed?
History
Description
Recognition of patterns
Testing
- Standard- biochemical, chromosome structure
- Microarray now standard
- Targetted testing
- Moving to trio-based exome/genome
What signs of genetic condition may manifest in the head?
Shape
Size: macrocephaly, microcephaly
Ear position - Low set, posteriorly rotated indicates lack of maturity
What signs of genetic condition may manifest in the eyes?
Hypertelorism
-Inner canthal distance ICD and inter-pupillary distance IPD increased
Telecanthus/epicanthic folds
-ICD and IPD increased
EYES
What signs of genetic condition may manifest in the hands?
Finger length
Digital abnormalities
Palmar creases
Examples Marfan syndrome, Down syndrome
What is the hand anomalies in Marfan’s Syndrome?
Long, thing fingers
MF/THL usually >44%
What are the words used describe long and short fingers?
Arachnodactyly
Brachydactyly
What is polysyndactyly and what is a cause?
Conjoined and extra fingers or toes
Hox D13
What is acrocephalopolysyndatyly and what is a cause?
Premature closing of cranial sutures commonly along with syndactuly (fusion of fingers or toes)
Greig/GLI3
Tall forehead
Polydactyly (multiple)
Syndactyly (joined)
What are sequences?
One abnormality leads to another, can have multiple causes
What is the Pierre-Robin sequence?
Small chin to cleft palate
What is the foetal akinesia sequence?
Reduced foetal movement Reduced breathing Contractures Clefting Lung hypoplasia
What is deformation and disruption?
Pattern of development normal to start with but becomes abnormal
Deformation: Organ parts are there
Disruption: Parts of organ/body part absent
What is an 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
Vaters syndrome
What are 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
How might you genetically investigate a learning disability?
Microarray
Fragile X - for learning disability
Targetted tests driven by phenotype (cheaper)
Trio based Exome vs. trio-base genome analysis
- Funding remains an issue
- Trio-based exome in Scotland and genome in England!
What are the signs of 22q11 deletion?
CATCH 22
C - Cleft palate A - Abnormal facies T - Thymic hypoplasia/immune deficiency C - Calcium H - Heart problems
We all have variation in our genome so how can we test thousands of genes and find the cause of the intellectual disability?
Trio-based testing compares parents with child to filter out silent variations
- Exons are targeted
- Only relevant parts of genome targeted
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
