Congenital heart disease Flashcards
Congenital heart disease is the most common form of what?
birth defect ( approx 1 per 100)
Congenital heart disease may be?
Isolated/Non-syndromic
Syndromic
What factors comprise Isolated/Non-syndromic congenital heart disease?
No other malformations
No family history
Probably polygenic/environmental factors
What factors comprise Syndromic congenital heart disease?
Family history (approx 3-5% of cases but may be different CHD)
Not dysmorphic
No other malformations
There may be some people with isolated congenital heart disease, with no other abnormalities, with a family history a related or different heart problem.
True or false
True
What is a syndrome?
A group of symptoms which consistently occur together, or a condition characterised by a set of associated symptoms.
What are four causes of a syndrome?
Chromosomal
Genetic
Unknown/associations
Maternal factors
Approximately what percentage of children with a congenital heart disease experience an underlying syndrome?
30%
What represents a syndromic form of congenital heart disease?
Certain types of heart lesion are more frequent
E.g. Truncus Arteriosus. Tetralogy of Fallot
Any other structural abnormalities?
+/- Family history of syndrome?
What is the purpose of investigating whether congenital heart disease is syndromic?
Prognosis and options Associated problems/abnormalities Inform clinical management Recurrence risk Specific treatments? Pathophysiological insights
What types of heart lesion are low risk of syndromic condition?
Transposition of the great Arteries
Total anomalous pulmonary venous drainage
What types of heart lesion are high risk of syndromic condition?
Tetralogy of Fallot
Ventricular septal defect
Truncus arteriosus
What is the current Pregnancy Screening in the UK?
11-13 weeks – Combined test to give a risk for trisomy 21 , 13 and 18
Nuchal translucency measurement,
PAPP-A and beta HCG levels
combined with maternal age
20 week fetal anomaly scan with 4 chamber view of the heart
What is increased Nuchal Translucency (NT) associated with?
Downs Syndrome
Chromosomal abnormalities
Congenital Heart Disease (any)
Other genetic (syndromes)
Chance of adverse outcome increases with increasing nuchal thickness
True or false
True
What forms of genomic variation is found in congenital heart disease?
Whole chromosomal abnormalities
Copy number variants
Insertions and duplications
Single nucleotide variants
What percentage of all children with a congenital heart disease have a chromosomal abnormality?
What do these include?
What percentage deviate from this condition?
10.8%
trisomy 21 (62%) trisomy 18 (15%) trisomy 13 (6.4%)
1.6%
What percentage of children with downs syndrome/ trisomy 21 have a congenital heart disease?
What is the most common heart defect?
What are other heart defects?
40-50%
atrioventricular septal defect, or AV canal defects (45%)
ventricular septal defects (35%),
secundum atrial septal defects (8%),
patent ductus arteriosus (7%).
tetralogy of Fallot (4%)
There is an increased risk presented of down syndrome with combined antenatal tests/clues.
What do these include?
What are non genetic tests?
Maternal age- INCREASED
serum free β-human chorionic gonadotrophin
(free β-hCG) - INCREASED
Pregnancy associated plasma protein A
(PAPP-A) - DECREASED
NIPT result
Absent nasal bone
Short femurs
What is Edwards syndrome caused by?
Trisomy 18 defect
What type of congenital heart defects are presented in trisomy 18?
and clues on antenatal scan
Type of lesion: VSD with Aortic override, unusual AV valves , DORV, …’dysmorphic’ heart
Small baby with small head Increased risk on combined test ‘strawberry’ shaped skull Rocker bottom feet exomphalos
What is Patau’s syndrome caused by?
Trisomy 13 defect
What are types of congenital heart defects in trisomy 13 and clues on antenatal scan?
VSDs, AVSD,
Increased risk on combined test
Polydactyly
Holoprosencephaly
Cleft lip
Small baby with small head
What are trisomy 13 and 18 increased risk with combined test include?
Maternal age INCREASED
serum free β-human chorionic gonadotrophin
(free β-hCG) DECREASED
pregnancy associated plasma protein A
(PAPP-A) DECREASED
Nuchal translucency INCREASED
What genetic defect leads to turner syndrome?
Karyotype 45,X0 ( or variations/mosaicism)
> 90% of women with a baby with turner syndrome miscarry due to what?
Fetal hydrops
What are antennal clues of turner syndrome?
Markedly increased nuchal translucency (>5mm)
Renal anomalies – horseshoe kidney
Pedal oedema of hands & feet ( 3rd trimester)
Fetal hydrops
What is the prevalence of cardiac malformations in babies with Turner syndrome?
What is the most common heart defect?
What are other heart defects?
approx 30%.
mostly left heart outflow tract obstructions
bicuspid aortic valve (16%) coarctation of the aorta (11%). aortic valve disease (3.2%) hypoplastic left heart partial anomalous pulmonary venous drainage had the highest relative risk.
Trisomies/monosomies are rarely inherited
True or false
True
Chromosomal abnormalities are not related to maternal age
True or false
False
Related to maternal age
Any other chromosomal imbalance – important to check both parents as will affect recurrence risk
True or false
True
Approximately 10% of babies congenital heart disease harbour a copy number variant for which the cause is unknown
What are the most common?
1q21.1,
7q11.23,
8p23.1,
11q25, 1
5q11.2, and
22q11.2.
What test be used to detect small deletions or duplications?
Microarray
Congenital heart disease is reported in approximately what percentage of babies with DiGeorge syndrome (22q11 microdeletion)?
What are the known cono-truncal’/left outflow tract heart defects?
80%.
tetralogy of Fallot, pulmonary atresia with ventricular septal defect, truncus arteriosus/common arterial trunk interrupted aortic arch, isolated anomalies of the aortic arch, ventricular septal defect.
22q11 Deletions were found in:
Approx 1 in 2 of patients (50.0%) with interrupted aortic arch
Approx 1 in 3 ( 33%) of patients with common arterial trunk
Approx 1 in 6 (15%) of patients with tetralogy of Fallot
What are clinical features of 22q11 microdeletion 1 in 4000 livebirths?
Immunodeficiency
Nasal Speech
Learning difficulties
Short stature
Cleft Palate/ Pierre Robin sequence
Kidney abnormalities
Hypocalcaemia
Psychiatric abnormalities
(30% develop schizophrenia-like psychoses)
What is Williams Syndrome caused by?
Microdeletion 7q11.23
How do you test for 22q11 microdeletion?
Can not see on normal chromosome analysis (karyotype)
FISH
but now superseded by
Array CGH
Soon…….NIPT.
Congenital heart disease is experienced by 80% of babies with Williams Syndrome.
What does this include?
75% supravalvular aortic stenosis
25% supravalvular pulmonary stenosis
What are characteristic features of Williams syndrome?
Characteristic Facial features
Developmental delay
Overfriendly personality
Hypercalcaemia (15%)
Jin SC, Homsy J, Zaidi S, et al. Contribution of rare inherited and de novo variants in 2871 congenital heart disease probands. Nat Genet 2017 found what?
ONLY 8% of CHD had de novo variants (after excluding chromosomal and CNVs)
~3% of isolated CHD
~28% with both neurodevelopmental and extra-cardiac congenital anomalies
rare inherited mutations in 1.8%
Autosomal Dominant…
Manifest in HETEROZYGOUS form
Multiple generations affected (vertical transmission)
Male to male transmission
50% risk to offspring
Reduced Penetrance
What are Autosomal Dominant conditions associated with Congenital Heart Disease e.g?
How may these appear?
Noonan syndrome
Holt Oram syndrome
Alagille Syndrome
May be inherited OR de novo
How many Noonan syndrome causative genes are known? What does this lead to?
Several genes >23 so testing in pregnancy can be difficult
What are characteristics of Noonan syndrome?
Short stature
Learning difficulties
Webbed neck ( markedly increased nuchal translucency)
What congenital heart defects are noted in Noonan syndrome?
Pulmonary stenosis (2nd/3rd trimester) Atrial septal defect Tetralogy of Fallot Hypertrophic Cardiomyopathy (3rd trimester)
There is clinical overlap between Noonan syndrome and which other rasopathies?
Cardio-facio-cutaneous syndrome
Costello syndrome
(Neurofibromatosis type 1)
What genes are affected in the rasopathies
H-RAS K-RAS SOS1 Neurofibromin BRAF RAF-1 MEK 1/2 SHP2
What are antennal clues of Noonan syndrome?
Risk increases with what? …
Who should be looked at and why?
Markedly increased nuchal translucency often >5mm and persists (Vigneswaran et al., 2017)
Type of heart lesion (often in 3rd trimester)
Polyhydramnios
Pleural effusions/Fetal hydrops/agenesis ductus venosus
Hydronephrosis
Relative macrocephaly
Short femurs
Paternal age
Parents, they may be affected
Who should be looked in relation to Tuberous Sclerosis and why?
What are antennal clues of Tuberous Sclerosis?
Look carefully at parents- highly variable (BUT 50% de novo)
MULTIPLE cardiac rhabdos- nearly always TS
But beware – they may become multiple OR they may look single but on post mortem they are found to be multiple
Tubers on brain – 3rd trimester only mainly seen on fetal MRI.
Genetic testing is improving so now helpful two genes TSC1 and TSC2
50% risk of seizures/autism/ severe ID
What are three features of Holt Oram syndrome?
ASD/AVSD/TOF
Radial ray defect
+/- family history
Differential diagnosis of CHD with radial ray defect
Bilateral Holt Oram syndome ( dominant and de novo) TAR syndrome ( recessive) Fanconi anaemia (recessive) VACTERL association
Unilateral
Trisomy 18 ( sporadic)
Fetal valproate syndrome
Cornelia de Lange
Autosomal Recessive….
Manifest in HOMOZYGOUS/ COMPOUND HETEROZYGOUS form
Carriers not affected
Usually one generation affected (horizontal transmission)
May be consanguinity
e.g. cousin marriages
What are Autosomal Recessive conditions associated with Congenital Heart Disease?
Ellis Van Creveld syndrome
AVSD
ASD
What are clues of Ellis Van Creveld syndrome?
Short long bones
Narrow thorax
Polydactyly
What are Non-Genetic causes/Tetratogens of congenital heart disease?
Fetal alcohol
Maternal diabetes
Maternal drugs e.g.anticonvulsants esp. Sodium valproate,
IVF/ICSI
What are antennal clues of Fetal Alcohol Syndrome?
Growth retardation including microcephaly Brain malformations Agenesis of the corpus callosum Limb defects Cardiac abnormalities
Maternal history!!
In Fetal Valproate Syndrome what risk is there of multiple congenital malformations ?
10.7%
dose-dependent increased risk
Four fold increased risk of CHD
Mainly Septal defects and valvular problems
No consistent type of defect
What are specific genes for non-syndromic CHD?
NKX2.5 - ASD, atrioventricular block, ventricular septal defect (VSD), Ebstein anomaly, and tetralogy of Fallot (TOF).
GATA4, a transcription factor - ASD, VSD, and pulmonary stenosis.
TBX1 - TOF, patent ductus arteriosus, and interrupted aortic arch
TBX20 - ASD, VSD, valve defects, and impaired chamber growth.
MYH6, which codes for an alpha myosin heavy chain (ASD)
Notch 1 - valve formation (bicuspid aortic valve and aortic stenosis)
