what is why is it paediatric different to adult …...anomaly face, cayler, sedlackova, catch22,...
TRANSCRIPT
Rik De DeckerRed Cross Children’s Hospital
What is paediatric cardiology?
What is paediatric cardiology?
Why is it different to adult cardiology?
Why is it different to adult cardiology?
One fine day…
• You are seeing Mrs Smith and her 2-week old son, John.
• He is very jaundiced.
• She says that his stools are chalky white.
• His lips and tongue also seem cyanosed, and he has an obvious heart murmur.
He looks a little unusual…
Mrs Smith asks 4 crucial questions…
1. What’s wrong?2. What will happen (now and later)?3. Why? 4. Will it happen to our next child?
(or … who’s to blame?)
Paediatric cardiology is different
• Congenital heart abnormalities– genetic
– teratogenic
• Associated abnormalities and syndromes
• Age plays a role– time of onset
– changes over time
• Acquired heart disease– acute rheumatic fever
– myocarditis / cardiomyopathy
– endocarditis
A brave new world…
• Embryology
• Genetics
• Foetal circulation– changes at time of birth
• Anatomy
• Clinical signs (and symptoms)
• Investigation
• Treatment, especially surgery!
1. Function
2. Substrate
3. Aetiology
3 approaches…
1. function• cyanosis or not• heart failure or not• arrhythmia• risk of death
2. substrate• gross structure• cardiomyocytic
What’s wrong?What’s wrong?
What can be done?What can be done?
3. aetiology3. aetiology
congenital abnormality
chromosomal
monogenic
polygenic
multifactorial
environmental
microdeletional
Why?Why?
Next child?Next child?
only a firm diagnosis allows accurate genetic counselling
examinationgenetictesting
pedigree
genetic counselling
diagnosis
clinical management
GENETICS
Spectrum of genetic causes of CHD
• Chromosomal– aneuploidy
– deletions
– other cytogenetic abnormalities
• Single gene disorders
• Other syndromic conditions of unknown genetic aetiology
• Nonsyndromic CHD
The spectrum of
congenital heart disease
GENETIC ENVIRONMENTAL
chromosomal
Trisomy 21
• usually (simple) balanced AVSD
• also VSD, PDA
• AVSD/Tetralogy
• genetic aetiology not well understood
Trisomy 18 & 13
• VSD, ASD, PDA in 80%
• cardiac surgery not usually offered
Turner syndrome
• coarctation of the aorta
• ASD
microdeletion syndromes
1. Tetralogy of Fallot
2. Right aortic arch
3. Laryngeal incompetence
4. Hypocalcaemia
5. Seizures
6. Cerebral atrophy
7. Recurrent infections
8. Feeding difficulties
9. Gastro-oesophageal reflux
10. Hyperactivity
11. Speech difficulty
12. Motor developmental delay
del22q11.2 syndromeaka
DiGeorge, Shprintzen, velocardiofacial, Takao, conotruncal anomaly face, Cayler, Sedlackova, CATCH22, Strong, …
Cardiac findingsCardiac findingsVentricular septal defect
Atrial septal defect
Pulmonic atresia or stenosis
Tetralogy of Fallot
Right sided aorta
Truncus arteriosus
Patent ductus arterious
Interrupted aorta
Coarctation of the aorta
Aortic valve anomalies
Aberrant subclavian arteries
Vascular ring
Anomalous origin of the carotid artery
Transposition of the great vessels
Tricuspid atresia
Genotype-phenotype correlation obscure
Williams syndrome
• supra-valvar aortic stenosis
• peripheral pulmonary stenosis
• elastin gene deletion
• chromosome 7 FISH
single gene disorders
Marfan syndrome
• aortic root dilatation
• MV prolapse
• fibrillin gene mutation
Noonan syndrome
• PTPN11 gene mutation in some (50%)
• pulmonary stenosis
• hypertrophic cardiomyopathy
John Smith has…
– jaundice (resolved)– butterfly vertebrae– Tetralogy of Fallot (repaired)
• JAGGED 1 mutation• sporadic• autosomal dominant
Alagille syndromeAlagille syndrome
EMBRYOLOGY
In the beginning...
Moorman et al. 2007 Phil Trans R Soc B 362: 1257-1265
Gastrula
Moorman et al. 2007 Phil Trans R Soc B 362: 1257-1265
Fo
ldin
g o
f
em
bry
on
ic
dis
k
heart
early development: a tug-of-war
• heart develops from a few mesodermal progenitor cells
• cardiac precursor zone defined by distinct gradients of genetic activity
• competing activating and inhibiting signals
• “all-or-nothing” phase
Harvey RP Nat Rev Genet 2002; 3:554-556
Männer J The Anat Rec 2000;259:248-262
2 heart fields!
• primary heart field develops atrial and left ventricular structures
• under control of NKX2.5
• secondary heart field lies more anteriorly and medially
• not derived from the cardiac crescent
• develops outflow tract and right ventricle
• under control of FGF10 and TBX1
Harvey RP Nat Rev Genet 2002; 3:554-556
The old embryology
arterial trunk
bulbus cordis
ventricle
atrium
sinus venosus
Heart tube
formation
Männer J The Anat Rec 2000;259:248-262
Cardiac loopingthe sequential
model
Männer J The Anat Rec 2000;259:248-262
From…to…Moorman AFM & Christoffels VM Physiol Rev 2003;83:1223-1267.
De la Cruz et al. 1977 and 1985. J Anat.
1. The heart tube contains all the cardiac precursors
2. Looping is the whole story
3. Development is linear
4. The septa are curtains dividing chambers
5. etc...
Some common misconceptions
modular chamber formation - not linear
• complex interplay of overlapping gene products form individual segments
• genes are region-specific• each chamber has intrinsic developmental properties
• chambers can be considered as modularelements
Bruneau BG Clin Genet 2003;63:252-261.Harvey RP Nat Rev Genet 2002; 3:554-556
whole-mount FISH
An explosion of knowledge!
• Recent confluence of:– description of the diverse genetic aetiologies of syndromic CHD
– the completion of the human genome, and– genomes of experimental animals– genetic databases and bioinformatics– molecular embryology, using– knock-in and knock-out animal models– 3D modelling and animation– microvideofluoroscopy
The ballooning model
development of a 4-chamber heart with 2 parallel flow circuitsfrom 1 segmented tube
the ballooning model
• old sequential model was a “fatal assumption” • new model based on:
– morphological,– functional,– flow &– genetic data
• requires the modular concept of chamber development – modules added during evolution– chambers selectively altered by site-specific genes
the linear heart tube
• poorly contractile• peristaltic• poorly coupled • slowly conducting• high automaticity
the fish heart
linear tube NOT folded
ballooning out of myocardium which is:
• rapidly conducting
• fast-contracting• coupled
• low automaticity
RV develops as a new
evolutionary structure
downstream of the P-ring P-ring
the mammalian heart
embryonic blood flow
P ring
blood is highly viscous
flow is laminar andparallel
P ring
How is all this controlled?
Acvr2b (activin A receptor, type IIB)* Laterality defects,* TGA, DORV, PTA
Agpt (angiopoietin 1) Atrial dysgenesis, ASD, venous malformation (cardinal vein obstruction)
Bmp4 (bone morphogenic protein 4) AVSD
Bmpr2 (bone morphogenic protein receptor, type II) PTA, semilunar valve dysgenesis
Cited2 (Cbp/p300-interacting transactivator, with Glu/Asp-rich carboxy-terminal domain, 2)
ASD, VSD, DORV, PTA
CRELD1 (cysteine-rich with EGF-like domains 1)* AVSD*
Cspg2/versican/hdf (chondroitin sulfate proteoglycan 2) CT hypoplasia
Dvl2 (disheveled homologue 2) PTA, TGA
Ece1 (endothelin converting enzyme 1) IAA, VSD, DORV, PTA
Edn1 (endothelin 1) IAA, VSD
Egfr (epidermal growth factor receptor) AS, AI
Erbb2 (erythroblastic leukemia viral oncogene homologue 2) Noncompaction, aberrant trabeculation
Erbb3 (erythroblastic leukemia viral oncogene homologue 3) AV hypoplasia
Endra (endothelin receptor type A) IAA, VSD, DORV, PTA, TGA
Fgf8 (fibroblast growth factor 8) DORV, PTA, ASD, VSD, AV valve atresia, arch hypoplasia
Foxc1 (Fkh1/forkhead box C1) Aortic arch abnormalities
Foxc2 (Mfh1/Fkh14/forkhead box C2) Aortic arch abnormalities
Gata4 (GATA binding protein 4)* ASD,* VSD, cardia bifida, ventral morphogenesis
Gja1 (connexin43/gap junction membrane channel protein 1)* RVOT obstruction, aberrant coronary patterning; heterotaxy*
Hand1 (eHand/heart and neural crest derivatives expressed 1) Looping abnormality
Hand2 (dHand/heart and neural crest derivatives expressed 2) RV hypoplasia, Ao arch hypoplasia, trabecular abnormality
Has2 (hyaluron synthase 2) Absent AV cushions and trabeculae
Hoxa3 (Hox-1.5/homeobox A3) CT abnormalities
Hspg2 (perlecan/heparin sulfate proteoglycan of basement membrane)
TGA/IVS, coronary anomalies
Jag1 (jagged 1)* PS, VSD, TOF, Alagille’s syndrome*
Madh6 (Smad6/mothers against decapentaplegic homologue 6) CT septation defects
Nf1 (neurofibromatosis 1) EC cushion defect, DORV
Nfatc (nuclear factor of activated T cells, cytoplasmic 1) VSD, valve defects
Nkx2–5 (Csx/NK2 transcription factor related, locus 5)* ASD,* VSD, TOF, EP
Nr2f2 (COUP-TFII/nuclear receptor subfamily 2, group F, member 2)
Atrial dysgenesis, ASD, venous malformation (cardinal vein obstruction)
Nrg1 (neuregulin 1) Noncompaction, dysmorphic trabeculae
Nrp (neuropilin-1) TGA, PTA
Ntf3 (neurotrophin 3) PTA, IAA, CT defects
Pax3 (paired box gene 3) PTA, CT defects
Pcaf (p300/CBP-associated factor) PTA, CT defects
Pdgfr (platelet-derived growth factor receptor, polypeptide) PTA, DORV, VSD, noncompaction
Pitx2 (paired-like homeodomain transcription factor 2) Laterality, AVSD, PTA, TGA, DORV
Rar (retinoic acid receptor, ; RAR1/ß2, /ß2, compound mutants similar)
IAA, VSD, PTA, DORV
Rarß (retinoic acid receptor, ß) CT defects, VSD
Rar (retinoic acid receptor, ) CT defects, VSD
Rxr (retinoid X receptor, ) ASD, VSD, AVSD, noncompaction, PTA, AP window
Sema3c (semaphoring 3C/sema domain, immunoglobulin domain, short basic domain, secreted)
IAA, PTA
Sox4 ([sex determining region Y]-box 4) AVSD, TGA, semilunar valve defects, PTA
Tbx1 (T-box 1)* DGS*
Tbx5 (T-box 5)* HOS*, ASD, VSD, TOF, EP
Tead1 (Tef-1/TEA domain family member 1) Noncompaction, trabecular abnormality
Tek (Tie2/endothelial-specific receptor tyrosine kinase)* Venous malformations*
Tgfß2 (transforming growth factor, ß2) VSD, DORV
Tgfßr3 (transforming growth factor, ß receptor III/ß glycan) Decreased cushion mesenchyme transformation
Vcam1 (vascular cell adhesion molecule 1) Noncompaction, VSD
Zfpm2 (FOG2 [friend of GATA] 2/zinc finger protein, multitype 2)
TA, ASD, VSD, PS, TOF, AVSD
Gene CHD
Gruber PJ & Ebstein JA Circ Res 2004;94:273-283.
Aetiology leads to control…?
Can we manipulate heart development?Canadian mandatory folate fortification 1998
The foetal circulation
Attitudinally Appropriate
ANATOMY
The Valentine Heart