Congenital Abnormalities

Question 1

What are the most common serious congenital disorders?

Answer 1

1) Heart defects
2) Neural tube defects (NTDs)
3) Down syndrome

Question 2

What are the types causes of congenital anomalies (although in many cases it is difficult to identify their cause)?

Answer 2

1) Genetic
2) Infectious
3) Environmental

Question 3

How can congenital rubella syndrome be prevented?

Answer 3

Timely vaccination of mothers during childhood and the reproductive years

Question 4

What are key ways to prevent and treat many birth anomalies?

Answer 4

1) Adequate intake of folic acid
2) Iodine
3) Vaccination
4) Adequate antenatal care

Question 5

What are birth defects/congenital disorders/malformations?

Answer 5

Structural or functional anomalies incl. metabolic disorders, which are present at the time of birth

Question 6

What % of recognised pregnancies (more bc many people don’t know they are pregnant e.g. in first 2 weeks) are lost before 12 weeks gestation (first trimester) ?

Answer 6

15%

Question 7

Why do spontaneously aborted pregnancies occur?

Answer 7

• 80-85% have gross structural abnormalities

- 50% chromosomal abnormalities - trisomy, monosomy, triploidy

Question 8

What does a malformation signify?

Answer 8

That fetal growth and development did not proceed normally due to underlying genetic, epigenetic or environmental factors that altered the development of a particular structure

Question 9

What are causes of malformations?

Answer 9

1) Monogenic/Mendelian (7.5%) e.g. achondroplasia (AD), achondrogenesis (AR)
2) Chromosomal (6%) e.g. T21
3) Multifactorial (20%) e.g. NTDs, isolated congenital heart disease, cleft lip and palate

Question 10

What are genetic causes of malformations?

Answer 10

1) Ectrodactyly Ectoderm dysplasia clefting (EEC) - P63
2) Diastrophic dysplasia - SLC26A2
3) Apert syndrome - FGFR2 - complete syndactyly of digits of hands
4) Grieg syndrome - GLI3

Question 11

What are environmental causes of malformations?

Answer 11

1) Teratogens e.g. fetal valproate syndrome (similar symptoms to T21)
2) Thalidomide
3) Maternal medication

Question 12

What is diabetic embryopathy caused by?

Answer 12

Poorly controlled maternal diabetes (hyperglycaemia in utero - if mum didn’t have diabetes, could be genetic

Question 13

What are the clinical features of diabetic embryopathy?

Answer 13

1) Midline facial defects
2) Microtia (underdevelopment of ears)
3) Microsomia
4) Large or small birth weight
5) CNS malformations
6) NTDs

Question 14

What are examples of congenital infections leading to specific syndromes/problems resulting from infection in pregnancy?

Answer 14

1) Zika
2) CMV
3) Rubella

Question 15

What are clinical features of congenital zika syndrome?

Answer 15

1) Microcephaly
2) Problems with vision and hearing
3) Problems moving limbs and body
4) Damage to the brain (CNS defects)
5) Seizures
6) Problems with feeding (difficulty swallowing)

Question 16

What is a feature of congenital CMV?

Answer 16

Significant neurological disorders

Question 17

What are the 3 clinical features of congenital rubella syndrome?

Answer 17

1) Microcephaly
2) PDA (patent ductus arteriosus)
3) Cataracts

Question 18

What are syndromes?

Answer 18

Collections of consistent recognisable patterns of abnormalities, not necessarily genetic

Question 19

What are dysmorphisms?

Answer 19

• Congenital malformations that have abnormal morphology
• > 2400 described dysmorphic syndromes caused by single gene defect and chromosome imbalances
• Syndrome may be associated with developmental delay

Question 20

What is the main cause of learning difficulties/intellectual disability/developmental delay?

Answer 20

Chromosomal abnormalities esp. Down’s syndrome (but many unknown causes)

Question 21

What is the baseline rate of major congenital abnormality?

Answer 21

1-2%
- Varies based on certain background facts e.g. poorly controlled diabetes, teratogenic drugs, previous baby with anomaly

Question 22

What abnormalities can be detected by US by organ?

Answer 22

1) Brain - acrania, holoprosencephaly
2) Spine - open spina bifida
3) Face - facial cleft, anopthalmia
4) Neck - cystic hygroma
5) Thorax - congenital diaphragmatic hernia
6) Abdominal wall - exomphalos, gastroschisis
7) Urinary tract - bilateral renal agenesis, urethral obstruction
8) Extremities - club foot, arthrogyposis
9) Skeleton - skeletal dysplasia, achondroplasia

Question 23

Why do you want to detect serious cardiac diseases on US?

Answer 23

So that the baby can be born at a specialist cardiac centre

Question 24

What congenital heart diseases can be seen on a four chambers view on an US?

Answer 24

1) Atrioventricular septal defect
2) Hypoplastic left heart syndrome
3) Ventricular septal defect
4) Ebstein’s anomaly

Question 25

What congenital heart diseases can be seen on a great vessels view on an US?

Answer 25

1) Transposition of the great arteries 2) Tetralogy of Fallot 3) Common arterial trunk 4) Coarctation of the aorta 5) Aortic valve stenosis

Question 26

Acrania - diagnostic features on US, prognosis, prevalence

Answer 26

- US diagnosis = absence of ossified skull at 12 weeks or anencephaly at 16 weeks - Prognosis - lethal condition within first week of life (always riskier to stay pregnant than to terminate pregnancy) - Prevalence = 1:1000 at 12 weeks

Question 27

Alobar holoprosencephaly - diagnostic features on US, associated abnormalities, prognosis, prevalence

Answer 27

- US diagnosis = forebrain abnormalities in transverse views - Associated abnormalities - T18 and T13 in > 50% of cases, genetic syndromes 20% - Prognosis - usually lethal in first year of life - Prevalence = 1:1300 at 12 weeks, 1:10,000 births

Question 28

Open spina bifida - diagnostic features on US, fetal therapy, prognosis, prevalence

Answer 28

- US diagnosis = detailed examination of spine from head to sacrum, characteristic brain/skull findings = lemon or banana sign - Fetal therapy - closure by fetal surgery (open vs fetoscopy) may improve motor and urologic function - Prognosis - 35% 5 year mortality, 25% stillborn, surviving = paralysis, incontinence, normal intelligence - Prevalence = 1:1000 at 12 weeks

Question 29

Cleft lip and palate - diagnostic features on US, associated abnormalities, prognosis, prevalence

Answer 29

- US diagnosis - detailed examination of face, can be picked up at 11-13 weeks, normally later - Associated abnormalities - 30% associated with variety of genetic syndromes - Prognosis - good if isolated, surgery at 3-6 months old, long term problems = dental, hearing, speech and psychological - Prevalence = 1:700, 50% (both lip and palate), 25% lip only, 25% palate only

Question 30

Diaphragmatic hernia - diagnostic features on US, associated abnormalities, fetal therapy, prognosis, prevalence

Answer 30

- US diagnosis = defect in diaphragm, abdominal contents in thorax - Associated abnormalities = 20% chromosomal (T18/13), 10% genetic syndromes (e.g. Pallister-Killian Syndrome), 20% other systems defects - Fetal therapy - fetoscopic placement of balloon in trachea at 26 weeks (current RCT) - Prognosis - good if isolated and mild, survival = <15% if severe, 50% if moderate, >90% if mild - Prevalence = 1:4000

Question 31

What should you do if you find one thing wrong on a fetal anomaly scan?

Answer 31

Keep looking to see if there are more, bc mild deformities may be ok but might also indicate other symptoms

Question 32

What two NTDs count for 90% of all NTDs?

Answer 32

Anencephaly and spina bifida

Question 33

Describe the types of anencephaly and spina bifida cases

Answer 33

- All anencephaly and most spina bifida cases are open defects where the neural tissue and meninges are exposed - 15-20% are closed where skin covers the defect and these are not detectable by biochemical testing

Question 34

What should be taken to prevent NTDs?

Answer 34

Folic acid - 2 months prior to pregnancy and 2 months into the pregnancy

Question 35

Describe the features of autosomal dominant inheritance

Answer 35

- 50% recurrence risk - High new mutation rate - Variable gene expression and penetrance due to e.g. modifier genes, response to DNA damage, carcinogens and hormonal/reproductive factors - Even in one family, different people with the same mutation will have different phenotypes depending on the penetrance

Question 36

Describe the features of autosomal recessive inheritance

Answer 36

- Often rare conditions - Usually in one generation - Increased risk with consanguinity - Parents usually obligate carriers - 25% recurrence risk at conception - ⅔ chance that unaffected sibling is a carrier - e.g. oculocutaneous albinism, MPS (Mucopolysaccharidosis), BBS (Bardet-Biedl syndrome)

Question 37

Describe the features of X-linked recessive inheritance

Answer 37

- 1 in 4 risk at conception - 1 in 2 risk for male - Males more severely affected - Possible lethality in affected male - Manifesting carrier female - e.g. Duchenne muscular dystrophy (DMD)

Question 38

How would you assess someone with a congenital abnormality?

Answer 38

1) FH - 3 generation family tree esp. for X-linked disorder incl. age of adult onset disorders 2) Pregnancy history - maternal illness e.g. diabetes, medicines incl. drugs and alcohol, scan data, birth history 3) Developmental history - e.g. motor or speech delay 4) PMH - e.g. repaired congenital heart disease, anal atresia 5) Examination - growth parameters, objective description of congenital malformations, dysmorphology assessment 6) Investigations - array CGH, mutation testing for suspected single gene

Question 39

What are the clinical features of DMD?

Answer 39

- Onset at 3-6 years - Progressive weakness - Pseudohypertrophy of calf muscles - Spinal deformity - Cardiopulmonary involvement - Mild to moderate MR - Significant weakness, disability and deformity leads to a lower life expectancy - Muscle weakness in all muscles leading to signs all around the body e.g. belly sticking out due to weak belly muscles and knees may and to take weight

Question 40

What are the features of myotonic dystrophy?

Answer 40

- Autosomal dominant - Distal myopathy - Prolonged muscle contraction e.g. problems with opening lids or relaxing hands after squeezing hands - Heart conduction defect - Diabetes - Early onset cataract - 40 repeats is normal, the more repeats you have the more severe and earlier onset the disease becomes (mild to adult to childhood to congenital) - Triplet repeat disorder - Expansion becomes worse when passed to offspring (parent may only have v mild symptoms)

Question 41

What are the features of congenital myotonic dystrophy?

Answer 41

- Genomic anticipation - Most severe form - Congenital hypotonia - Joint contractures (talipes) - Respiratory failure - Facial weakness - Swallowing difficulties - Developmental delay - Autism spectrum disorder - Massive expansion of myotonic dystrophy gene leads to severely hypotonic baby - At 16-18 week scan may see reduced mobility, contracture of knee, right hand clenched - Poor life expectancy, may terminate pregnancy

Question 42

What are the clinical features of Noonan syndrome?

Answer 42

- Facial dysmorphology - up slanting eyes, wider neck - Pulmonary stenosis - Short stature - Intellectual disability

Question 43

What are examples of mutations in genes which function in the same pathway that may cause similar but distinct clinical phenotypes (Noonan syndrome)?

Answer 43

Some phenotypic overlap with (genes interact with one another): - Neurofibromatosis type 1 - especially NF1 and valvular pulmonary stenosis (similar Noonan-like faces - AKA Watson syndrome) - Cardio-facial-cutaneous syndrome - more severe learning difficulties and sparse hair/lack of eyebrows - Costello syndrome - severe developmental delay and learning difficulties and increased risk of malignancy

Question 44

What are the clinical features of neurofibromatosis type 1 (variable expression)?

Answer 44

- Autosomal dominant - Caused by mutations (deletion) in the NF1 gene - Causes lumps/neurofibromas or v complex lumps on internal peripheral nerves called plexiforms - Freckling of eyes (Lisch nodules) - Coffee coloured patches (cafe au lait spots) - Bony defects incl. scoliosis and tibial bowing - Predisposition to developing tumours esp. optic gliomas on the optic nerve

Question 45

What are the two types of monogenic disorders?

Answer 45

1) Inherited/familial | 2) De novo

Question 46

What are examples of monogenic disorders?

Answer 46

1) Spinal muscular atrophy (SMA) 2) Cystic fibrosis (CF) 3) Duchenne muscular dystrophy (DMD)

Question 47

When would a prenatal referral be done for a monogenic disorder?

Answer 47

1) Due to FH of disorder | 2) Due to US indicators e.g. echogenic bowel may indicate CF