This is an autosomal dominant condition caused by defective fibrillin, a protein important to the integrity of connective tissue (see Figure 6.1). The relevant gene (FBN1) has been mapped to chromosome 15q21.1. The cardiac features are the most important and life-threatening aspects of Marfan syndrome, manifesting in childhood in 25% of those affected. The cardiac involvement is progressive in around one third of these children. Features include the major diagnostic criterion of dilatation of the ascending aorta with or without aortic regurgitation, and involving at least the sinuses of Valsalva or dissection of the ascending aorta. Minor diagnostic criteria for Marfan syndrome include mitral valve prolapse with or without mitral valve regurgitation, dilatation of the main pulmonary artery in the absence of another anatomic cause (before age 40), calcification of the mitral annulus (before age 40), and dilatation or dissection of the descending thoracic or abdominal aorta (before age 50).

Figure 6.1 Marfan syndrome—joint hypermobility.

Jones, Kenneth. 2005. Smith’s Recognizable Patterns of Human Malformation, 6th edition, p. 550.

Parental education regarding the importance of avoiding strenuous exercise and competitive or contact sports is important, and should begin before preschool, placing less emphasis on the importance of sporting activities. Non-strenuous activities should be encouraged (e.g. walking, fishing, golf). The symptoms of aortic dissection must be discussed, including chest pain and syncope.

In teenage years, important issues include consideration of beta blockers to slow the progress of aortic dilatation, and counselling to teenage girls about the risks of pregnancy, as rupture of the aorta can occur during pregnancy or at delivery. Angiotensin II receptor blockers (ARBs) have been used as an alternative to beta blockers, after an animal model found a metabolic defect of the aortic wall that improved with the use of ARBs; in 18 patients treated with ARBs for 12–47 months, there was a decrease in the rate of aortic root diameter change compared to when they were receiving beta-blocker therapy.

The clinical diagnosis of Marfan syndrome is based on major and minor criteria; there are four findings with major significance (all in bold and made to start with D):

Dilatation or dissection of aorta at level of sinuses of Valsalva

Displacement of lens (ectopia lentis)—directed upward; also early cataract formation

Dural ectasia (lumbosacral)

Dolichostenomelia: disproportionately long extremities; decreased upper to lower segment ratio (US:LS < 0.85 for older children/adults) or arm span to height ratio > 1.05; other diagnostic skeletal features—

Deformed spine (scoliosis > 20°, or spondylolisthesis)

Deformed sternum (pectus excavatum or pectus carinatum, requiring surgery)

Deep acetabulum with accelerated erosion (protrusio acetabulum)

Decreased elbow extension (< 170°) (in contradistinction to hypermobility of other joints)

Digit-related eponymous signs—(a) the thumb (Steinberg) sign, this being an extension of the whole distal phalanx of the thumb beyond the ulnar border of the hand when apposed across the palm (see Figure 6.2), and (b) the wrist (Walker–Murdoch) sign, this being overlapping of the distal phalanx of the thumb with the distal phalanx of the little finger when encircling the opposite wrist (see Figure 6.3)

Downward (medial) rotation of medial malleolus causing pes planus—four of these skeletal features are considered one major criterion

Distinctive facial features (dolichocephaly, down-slanting palpebral fissures, deeply set eyes (enophthalmos), decreased malar prominence (malar hypoplasia), diminished jaw (retrognathia)

Figure 6.2 Steinberg thumb sign.

Jones, Kenneth. 2005. Smith’s Recognizable Patterns of Human Malformation, 6th edition, Figure 2B.

Figure 6.3 Walker–Murdoch wrist sign.

Jones, Kenneth. 2005. Smith’s Recognizable Patterns of Human Malformation, 6th edition, Figure 2C.

The acronym MARFANS also can be used as an (alternative) aide-mémoire:

M. Mitral prolapse ± Mitral regurgitation

A. Ascending aorta dilatation (involving sinuses of Valsalva)/dissection/Arched palate (high arched, with tooth crowding)/Acetabuli (protrusio acetabuli)

R. Regurgitation of aorta/mitral/Retinal detachment/Reduced US:LS ratio

F. Fibrillin defective/Facial gestalt (dolichocephaly, down-slanting palpebral fissures, deeply set eyes (enophthalmos), decreased malar prominence (malar hypoplasia), diminished jaw (retrognathia)/Flat cheek bones/Flat cornea/Flexible joints (joint hypermobility)

A. Apical blebs (on CXR)/Air leaks (spontaneous pneumothorax)/Arachnodactyly

Near-sightedness (myopia)/Neurological involvement related to dural ectasia—stretching of dural sac in the lumbosacral region/Nerve entrapment—CSF leak from dural sac (causing postural hypotension and headache)

S. Scoliosis/Sternal deformity/Skeletal dolichostenomelia/Sacral dural ectasia

Noonan syndrome (NS)

NS is an autosomal dominant condition, associated with four genes. In 50% of cases, the associated gene locus is at 12q24.1, with mutations in PTPN11, the gene encoding the non-receptor type protein, tyrosine phosphatase SHP-2. The other genes are KRAS, SOS and RAF1. Almost all patients with NS have some cardiac defect, particularly a dysplastic (and often stenotic) pulmonary valve, which is more common with a PTPN11 mutation, or hypertrophic cardiomyopathy (HCM), which affects around 20–30% of NS children, but is less common with a PTPN11 mutation. The ECG frequently shows left-axis deviation and a dominant S wave over the praecordial leads, even in NS patients with no known cardiac disease; the cause for this is not known. Phenotypic features of NS include dysmorphic facial features, short stature, webbed neck and skeletal anomalies (see the short case on dysmorphism).

NS patients with dysplastic pulmonary valves can have rapid progression of pulmonary valvular obstruction and may require review more frequently than for non-NS pulmonary valve lesions. Also, NS-associated valve obstruction is more likely to require surgical intervention. Balloon valvoplasty is usually unsuccessful in abolishing the obstruction, and simple valvotomy may be inadequate. Often complete excision of the valve, resection of the right-ventricular outflow muscle, and occasionally an outflow tract patch may be needed. Atrial septal defects (ASDs) (Figure 6.10) and pulmonary artery branch stenoses may coexist with valvular pulmonary stenosis (Figure 6.4). Other infrequent findings with NS include ventricular septal defects (VSDs) (Figure 6.12) and tetralogy of Fallot (Figure 6.17 and Figure 6.16).

Figure 6.10 Physiology of atrial septal defect (ASD).

Circled numbers represent oxygen saturation values. The numbers next to the arrows represent volumes of blood flow (in L/min/m²). This illustration shows a hypothetical patient with a pulmonary-to-systemic blood flow ratio (Qp:Qs) of 2:1. Desaturated blood enters the right atrium from the vena cavae at a volume of 3 L/min/m² and mixes with an additional 3 L of fully saturated blood shunting left to right across the ASD; the result is an increase in oxygen saturation in the right atrium. Six litres of blood flows through the tricuspid valve and causes a mid-diastolic flow rumble. Oxygen saturation may be slightly higher in the right ventricle because of incomplete mixing at the atrial level. The full 6 L flows across the right-ventricular outflow tract and causes a systolic ejection flow murmur. Six litres returns to the left atrium, with 3 L shunting left to right across the defect and 3 L crossing the mitral valve to be ejected by the left ventricle into the ascending aorta (normal cardiac output). Behrman et al, 2007. Nelson Textbook of Paediatrics, 17th edition, Figure 419.1.

Figure 6.4 Physiology of valvular pulmonary stenosis.

Boxed numbers represent pressure in mmHg. Because of the absence of right-to-left or left-to-right shunting, blood flow through all cardiac chambers is normal at 3 L/min/m². The pulmonary-to-systemic blood flow ratio (Qp:Qs) is 1:1. Right atrial pressure is increased slightly as a result of decreased right ventricular compliance. The right-ventricle is hypertrophied, and systolic and diastolic pressure is increased. The pressure gradient across the thickened pulmonary valve is 60 mmHg. The main pulmonary artery pressure is slightly low, and poststenotic dilatation is present. Left heart pressure is normal. Unless right-to-left shunting is occurring through a foramen ovale, the patient’s systemic oxygen saturation will be normal. Behrman et al, 2007. Nelson Textbook of Paediatrics, 17th edition, Figure 420.1.

Figure 6.12 Physiology of a large ventricular septal defect (VSD).

Circled numbers represent oxygen saturation values. The numbers next to the arrows represent volumes of blood flow (in L/min/m²). This illustration shows a hypothetical patient with a pulmonary-to-systemic blood flow ratio (Qp:Qs) of 2:1. Desaturated blood enters the right atrium from the vena cava at a volume of 3 L/min/m² and flows across the tricuspid valve. An additional 3 L of blood shunts left to right across the VSD, the result being an increase in oxygen saturation in the right ventricle. Six litres of blood is ejected into the lungs. Pulmonary arterial saturation may be further increased because of incomplete mixing at right-ventricular level. Six litres returns to the left atrium, crosses the mitral valve, and causes a middiastolic flow rumble. Three litres of this volume shunts left to right across the VSD, and 3 L is ejected into the ascending aorta (normal cardiac output). Behrman et al, 2007. Nelson Textbook of Paediatrics, 17th edition, Figure 419.5.

Figure 6.17 Blalock–Taussig shunt in the patient with tetralogy of Fallot.

Circled numbers represent oxygen saturation values. The intracardiac shunting pattern is as described for Figure 423.1. Blood shunting left to right across the shunt from the right subclavian artery to the right pulmonary artery increases total pulmonary blood flow and results in a higher oxygen saturation than would exist without the shunt (see Fig. 423.1). Behrman et al, 2007. Nelson Textbook of Paediatrics, 17th edition, Figure 423.5.

Figure 6.16 Physiology of the tetralogy of Fallot.

Circled numbers represent oxygen saturation values. The numbers next to the arrows represent volumes of blood flow (in L/min/m²). Atrial (mixed venous) oxygen saturation is decreased because of the systemic hypoxemia. A volume of 3 L/min/m² of desaturated blood enters the right atrium and traverses the tricuspid valve. Two litres flows through the right-ventricular outflow tract into the lungs, whereas 1 L shunts right to left through the ventricular septal defect (VSD) into the ascending aorta. Thus, pulmonary blood flow is two thirds normal (Qp:Qs of 0.7:1). Blood returning to the left atrium is fully saturated. Only 2 L of blood flows across the mitral valve. Oxygen saturation in the left ventricle may be slightly decreased because of right-to-left shunting across the VSD. Two litres of saturated left-ventricular blood mixing with 1 L of desaturated right-ventricular blood is ejected into the ascending aorta. Aortic saturation is decreased, and cardiac output is normal. Behrman et al, 2007. Nelson Textbook of Paediatrics, 17th edition, Figure 423.1.

HCM in NS does not have a clearly defined natural history. HCM can become progressive in infancy, or may not develop or be recognised until late in childhood. Symptomatic HCM in NS can lead to sudden cardiac death, even in infancy. Treatment is as for non-syndromic HCM, including cardiac transplantation. See the section on familial HCM below.

The acronym NOONANS can be used as an aide-mémoire:

Neurodevelopmental problems: 25% learning disability, 10–15% special education, <30% mild intellectual impairment, 72% articulation problems, non-verbal abilities better than verbal, specific learning problems/Neuromuscular examination—hypotonia (floppy strong): joint hyperextensibility/Neurosurgical—Arnold–Chiari type I

O. Obstructive heart lesions: RVOT (pulmonary valve); LVOT (HCM)/Other: ASD, VSD, tetralogy of Fallot, coarctation of aorta, branch pulmonary artery stenosis

O. Ocular anomalies in up to 95%: strabismus, refractive errors, amblyopia, nystagmus; hypertelorism, epicanthic folds, droopy eyelids, vivid blue or blue–green irises

Neoplasia risk: juvenile myelomonocytic leukaemia (JMML); myeloproliferative disorders; Noonan-like/multiple giant-cell lesion syndrome (granulomas and joint and bone anomalies); hepatosplenomegaly (related to subclinical myelodysplasia)

A. Abnormal coagulation (33% have one or more defects)/Abnormal lymphatics: lymphoedema (hands/feet/scrotum/vulva), lymphangiectasia (lung, gut or testis)

Neck webbing, with low-set posteriorly rotated ears/Nipples appear low-set/Nephrological anomalies: duplex collecting systems, renal hypoplasia

S. Sternal deformity (superior carinatum, inferior excavatum)/Short stature (GH Rx)/Secondary sexual characteristics: delayed puberty, cryptorchidism in males/Skin findings: pigmented naevi (25%), café-au-lait patches (10%), lentigines (3%)

NS can be mimicked by other conditions with NS-syndrome-like facies, which can be related at a genetic level in some cases:

• Cardio-facial-cutaneous (CFC) syndrome (cardiac lesions—pulmonary valve stenosis; atrial septal defects); hyperkeratosis, haemangiomata, icthyosis. Four genes associated: BRAF (70–80%), MAPK1 and MAPK2 (10–15%), and KRAS (<5%).

• LEOPARD syndrome (Lentigines, ECG abnormalities [axis deviations, unilateral or bilateral hypertrophy, conduction abnormalities], Ocular hypertelorism, Pulmonary stenosis, Abnormalities of genitalia, Retardation of growth, and Deafness). Two genes associated: PTPN11 and RAF1; testing these finds mutations in 93% of affected people.

• Neurofibromatosis–Noonan syndrome; gene map locus 17q11.2; the clinical overlap between NFNS and NS is explained by the respective gene products, neurofibromin and SHP2, exerting their modulatory effects via a common pathway.

• Watson syndrome; gene map locus 17q11.2 (like NFNS, and NF1). Features: short stature, pulmonary valve stenosis, pigmented skin lesions (café-au-lait spots), intellectual development variable. Phenotype overlaps with NF1 as well as NS.

• Costello syndrome; gene map locus 11p15.5. Gene: the HRAS proto-oncogene; phenotypic overlap with NS and CFC. Features: short stature, pulmonary stenosis, HCM, hypertelorism, epicanthic folds, intellectual development variable.

22q11.2 deletion syndrome: neural crest—associated conotruncal defects

This includes the following syndromes: DiGeorge (DGS), velocardiofacial (VCFS), Shprintzen, conotruncal anomaly face (CTAF), Caylor cardiofacial, and autosomal dominant Opitz G/BBB.

Deletion of chromosome 22 is the most common chromosome deletion, affecting 1 in 4000 live births. The deletion most commonly spans three megabases of DNA and contains almost 30 genes. A wide variety of cardiac defects are described in patients with microdeletions in band 11 of the long arm of chromosome 22 (22q11 deletions). The acronym CATCH-22 (Cardiac defects, Abnormal facies, Thymic hypoplasia and T-cell deficiency, Cleft palate, Hypoparathyroidism and Hypocalcaemia) can be used as an aide-mémoire for those with such deletions. Other findings include renal anomalies, developmental delay and late-onset psychiatric problems. These children may be born with duct-dependent complex cyanotic heart disease. Around one third of children with non-syndromal conotruncal cardiac defects have 22q11 deletions as well. Deletions of 22q11.2 have also been identified in children with various forms of familial, and sporadic, congenital heart disease.

Dysmorphic facial features include a myopathic facial appearance, unusually shaped ears, a long nose with a broad bridge, a small mouth, micrognathia, short upward slanting palpebral fissures, and a cleft or high palate (may be accompanied by hypernasal speech).

With any patients with these anomalies, genetic assessment and counselling is warranted, with chromosomes and fluorescence in-situ hybridisation (FISH) for the 22q11.2 microdeletion. The parents should be tested for 22q11.2 deletion, and must be educated as to the associated problems (e.g. problems with the palate, immunodeficiency, learning difficulties, developmental delay), the likelihood of further syndromal traits developing and the risk of transmitting the deletion to their offspring (50%). The patient should have blood taken to check for hypocalcaemia, and abdominal ultrasound to assess renal anatomy.

The acronym CATCH-22 can be expanded to CATCHING, to include more features:

C. Cardiac: 74%; Conotruncal; 3 Ts, 3As, 3Ps (see text above); causes > 90% of all deaths

A. Abnormal face: long face, malar flatness, hypertelorism, hooded eyelids, ptosis, ear anomalies (overfolded helices, cupped, microtic, protruberant ears, preauricular pits), prominent nasal root, bulbous nasal tip, nasal dimple, asymmetric crying face)/Autoimmune diseases: juvenile idiopathic arthritis, Graves’ disease, vitiligo

T. Thymic hypoplasia, T-cell deficiency; 77% have immunodeficiency

C. Cleft palate, and other palatal anomalies: velopharyngeal incompetence (VPI), submucosal cleft palate (SMCP), bifid uvula, cleft lip; 69% have palatal problem/Craniosynostosis and other skeletal anomalies: hemivertebrae, polydactyly, extra ribs/Croup-like: laryngotrachealoesophageal anomalies—vascular ring, laryngeal web

H. Hypoparathyroidism/Hypocalcaemia/Hearing loss (conductive and sensorineural)

I. Intellectual issues: learning problems (non-verbal), 70–90%; mean full scale IQ 75–80; neuropsychological—ADHD, ASD; schizophrenia, bipolar, anxiety, depression/Impaired swallowing (dysmotile pharyngoesophageal area [derived from 3rd and 4th pharyngeal pouches]; nasopharygeal reflux, abnormal cricopharyngeal closure)

Neurological: unprovoked fits, neural tube defects, cerebellar atrophy, tethered cord/Nephrological: dysplastic kidneys, horseshoe kidney, duplicated kidney (37% in all)/Neoplasia: hepatoblastoma, neuroblastoma, Wilms, renal cell carcinoma

G. Growth hormone deficiency/Genitals: hypospadias, cryptorchidism, absent uterus/Gastrointestinal: atresias (oesophageal, jejunal, anal), malrotation, Hirschsprung/GP1BB mutation can cause coexistent Bernard–Soulier syndrome (BSS) (thrombocytopaenia and giant platelets); risk of bleeding significant

Williams syndrome (WS)

Williams syndrome is due to a deletion of a region of chromosome 7, termed the Williams–Beuren Syndrome Critical Region; it comprises 1.5–1.8 million base pairs and has 26–28 genes (see Figure 6.6). This area is predisposed to misalignment, during meiosis, of ‘duplicons’, which are low-copy-repeat blocks of homologous groups of genes and pseudogenes flanking the WBSCR. Hemizygosity for the elastin gene (ELN deletion) leads to the elastin arteriopathies supravalvular aortic stenosis (SVAS), peripheral pulmonary arterial stenosis (PPS) and other vascular stenoses. Hemizygosity for the gene LIM-kinase 1 leads to impaired visuospatial construction cognition. WS is a polyendocrine disorder that can involve all endocrine organs, and it is also a neurodevelopmental disorder. Children with this condition are friendly, outgoing and gregarious, are easily noticed and approach strangers readily. It is inherited as autosomal dominant. Cardiovascular conditions seen in WS include: SVAS, PPS, mitral valve prolapse, ventricular and atrial septal defects, renal artery stenosis with hypertension, and hypoplastic aorta. The mnemonic WILLIAMS HYPERCALCAEMIA has most of the salient features of WS:

W. Williams–Beuren Syndrome Critical Region (WBSCR); chromosome locus 7q11.2

I. Intelligence quotient (IQ) average 50–60/Impaired vision: reduced stereopsis

• Low tone (hypotonia)/Low pitched or hoarse voice, vocal cord paralysis

• Lax joints (joint hypermobility)/Loquacious, over-friendly, excessively empathic

I. Impaired feeding; tactile sensory defensiveness (difficulty with food textures); vomiting

A. ADHD symptomatology/Anxiety (somatisation can lead to abdominal pain)

M. Mitral valve prolapse (MVP)

S. Supravalvular aortic stenosis (SVAS)/Spine: scoliosis, kyphosis/Sternum: excavatum

HY. HYpercalcaemia, hypercalciuria, hypertension

P. Peripheral pulmonary arterial stenosis (PPW)/Puberty early (but not precocious)

E. Elastin arteriopathy (SVAS, PPS, aortic insufficiency, stenosis of mesenteric arteries)/Endocrine: hypothyroidism; IDDM in adults/Elfin face (see details below under A for appearance)

R. Renal anomalies (nephrocalcinosis, pelvic kidney)

C. Chronic otitis media (50%)/Characteristic personality: over-friendly, people-orientated

A. Audiological problems: high-frequency sensorineural hearing loss, hyperacusis (in 90%)

• Linear growth failure; postnatal growth rate 75% of normal/Loquacious personality

C. Cognitive: good verbal short-term memory, language; poor visuospatial construction

A. Appearance: broad brow, bitemporal narrowness, medial eyebrow flare, short palpebral fissures, epicanthic folds, blue stellate iris, short nose, full nasal tip, full cheeks, malar hypoplasia, long philtrum, full lips, wide mouth, small jaw, prominent earlobes

E. Eyes: hypotelorism, strabismus (50%), amblyopia, refractive errors (hyperopia in 50%)

M. Malocclusion, microdontia, enamel hypoplasia, widely spaced teeth, missing teeth

I. Intestinal problems: constipation, diverticulosis, coeliac disease

A. Abdominal pain: reflux oesophagitis; cholelithiasis; diverticulitis; ischaemic bowel disease

Figure 6.6 Williams syndrome.

Note the depressed nasal bridge, epicanthal folds, periorbital fullness, anteverted nares, long philtrum and prominent lips with large mouth. (A–C, From Jones KL, Smith DW: J Pediatr 86:718, 1975, with permission.) Jones, Kenneth. 2007. Smith’s recognizable patterns of human malformation, 3rd edition, p.122, Figure 1A.

Supraventricular tachycardia (SVT)

The commonest sustained tachyarrhythmia in children, SVT is caused mainly by an additional electrical connection between the atria and ventricle (accessory atrioventricular connection, AAVC) in those under 12; in teenagers, atrioventricular node re-entry tachycardia (AVNRT; has the functional equivalent of an extra connection within the AVN) may be a cause. Those with AAVCs often have ‘orthodromic’ tachycardia, with antegrade conduction down the atrioventricular (AV) node and retrograde conduction up the AAVC (the right way down the right path, the wrong way up the wrong path). Some patients have an AAVC that conducts in an antegrade fashion as well (giving ‘antidromic’ tachycardia, with retrograde conduction either up the AV node or the AAVC). Re-entry, the mechanism underlying these forms of SVT, requires two electrophysiologically distinct pathways around an insulated core, such as the AV valve annulus. Most cases of re-entrant SVT are sporadic.

Accessory connections include: (a) the concealed accessory connection, where the connection is not seen on ECG in normal sinus rhythm, and it conducts in a retrograde fashion from ventricle to atrium, a unidirectional retrograde accessory pathway; and (b) permanent junctional reciprocating tachycardia, where the accessory connection acts like a concealed connection, but the transmission through the connection is slow, such that during SVT the rate may be quite slow (130–150 beats/min) compared to other forms of SVT. Other additional pathways are named Wolff–Parkinson–White (WPW), Lown–Ganong–Levine (LGL) and Mahaim, as follows:

Wolff–Parkinson–White (WPW) syndrome is a combination of pre-excitation on surface ECG and episodic SVT, whether orthodromic or antidromic. In WPW, the ECG shows a short PR interval, a delta wave (initial slurring of the QRS complex) and a wide QRS complex. During episodes of tachycardia the ECG develops either a narrow QRS tachycardia with a retrograde P wave after the QRS (orthodromic SVT) or a wide QRS (antidromic SVT). Children with WPW can develop atrial flutter, and also have a small risk of sudden cardiac death (SCD) from extremely fast atrial tachycardias (e.g. atrial flutter or atrial fibrillation being conducted down the AAVC, producing ventricular tachycardia [VT] or ventricular fibrillation [VF]).

Lown–Ganong–Levine (LGL) syndrome is another form of pre-excitation and episodic SVT, where the ECG shows a short PR interval and normal QRS complex; in LGL, the upper AV node is bypassed by James fibres that connect the atrium and the bundle of His, producing a short PR, but the ventricles are depolarised normally.

Mahaim-type pre-excitation and episodic SVT is a third form, which has a long QRS with a delta wave, but a normal PR interval; here, the bundle of His is bypassed by Mahaim fibres, which connect the AV node and one of the ventricles.

Treatment modalities for acute SVT include vagal manoeuvres (e.g. Valsalva, blowing up balloons with nose occluded, blowing into the end of a syringe [trying to move/blow the plunger outward], application of icepack to face, doing a ‘headstand’, carotid body massage), IV adenosine (the preferred IV drug, given rapidly and can be increased incrementally) or IV propranolol, digoxin, procainamide or amiodarone. Adenosine is the treatment of choice in the haemodynamically unstable child; if unsuccessful, or there is difficult venous access, synchronised cardioversion (0.5–1.0 joule per kg) can be used. Verapamil is best avoided; IV verapamil is contraindicated in infants, in whom it can be lethal because it can produce AV block.

SVT in infants spontaneously resolves in the majority, and medical management is the first choice in the first year; also, transcatheter ablation has increased risk, and is avoided at this age. Beyond infancy, for long-term treatment, radio-frequency (RF) catheter ablation has a success rate, of around 90–95%. RF ablation comprises delivery of a high-frequency (500 kHz), low-energy electric current to the relevant cardiac area by an intracardiac catheter. This raises the temperature and burns the arrhythmia substrate. Risks of RF catheter ablation include inadvertent AV block and cardiac perforation; these are both very rare, the overall complication rate for RF ablation being below 4%. The other form of ablation is cryoablation, which does not cause unintentional heart block, but this enhanced safety has to be balanced against a potentially higher recurrence rate.

Long-term pharmacological treatments are aimed at modifying the conduction properties of the AVN, and usually involve beta blockers, digoxin or calcium channel blockers (however, digoxin and calcium channel lockers are contraindicated in those with WPW, as they can precipitate arrhythmias by enhancing AAVC conduction). For cases that are more difficult to control, other useful agents include the more potent antiarrhythmics, such as the sodium channel blocker flecainide (but this is avoided in structural or ischaemic heart disease), the combined beta blocker and potassium channel blocker, sotalol (but this can lead to QT prolongation and proarrhythmia), procainamide and amiodarone. In the absence of cardiomyopathy or structural heart disease, the prognosis for SVT is very good. WPW does have a small but real risk of SCD, the main risk indicator being symptoms (such as syncope or palpitations) in adults; 55% of asymptomatic children and adolescents become symptomatic by the age of 40, and symptomatic patients have an overall lifetime risk of 3–4% of SCD. All children with WPW should be referred to a paediatric electrophysiologist.

Long QT syndrome (LQTS)

Children with arrhythmias (e.g. sick sinus syndrome, severe bradycardia, complete AV block), congestive cardiac failure, myocarditis or anthracycline cardiotoxicity, or those on certain medications (e.g. several antiarrhythmics [especially quinidine], some antibiotics, diuretics [by causing acute/chronic hypokalaemia], promotility agents, [cisapride]) have an increased risk of developing LQTS, and subsequent ‘torsades de pointes’ (TdP) (twisting of points) ventricular tachycardia, which can present with Sudden death, Syncope or Seizures (the three Ss). Recent molecular breakthroughs are unravelling the congenital forms of LQTS.

Romano–Ward syndrome (RWS)

This autosomal dominant cardiac electrophysiological disorder is characterised by LQTS and T-wave abnormalities on ECG, and by TdP; TdP is usually self-terminating and causes syncope particularly with exercise or emotional stress, with no warning—sometimes at rest, or in sleep. TdP can degenerate to ventricular fibrillation (VF) and causes sudden death, or aborted cardiac arrest if defibrillated successfully. Molecular genetic testing can identify the genes associated with RWS that code for potassium or sodium channels: KCNQ1 (chromosome 11p15.5), KCNH2 (chromosome 7q35–q36), SCN5A (chromosome 3p21), KCNE1 (chromosome 21q22.1–q22.2), KCNE2 (chromosome 21q22.1) and SCN4B (chromosome 3p21). The first five account for 70% known mutations; the last is more recently described, and the proportion attributable to this is unknown. Three clinical phenotypes are recognised: LQT1 is due to mutations in KCNQ1 and KCNE1 causing IKs potassium channel dysfunction, and cardiac events triggered by exercise and emotion; LQT2 is due to mutations in KNH2 and KCNE2 causing IKr potassium channel dysfunction, and cardiac events triggered by exercise, emotion and sleep; and LQT3 is due to mutations in SCN5A, the cardiac sodium channel gene, causing INa channel dysfunction, and cardiac events triggered by sleep. Management for the LQT1 and LQT2 phenotypes is beta blocker or pacemaker if beta blocker produces symptomatic bradycardia; recurrence of events while receiving beta blockers is usually the result of inadequate dosing; for the LQT3 phenotype, implantable cardioverter–defibrillator (ICD); ICD may also be required for the LQT1 and LQT2 if resistant to beta blockers or there is a past history of cardiac arrest. Automatic external defibrillators should be readily available at home, at school and at work. It is very important these patients avoid drugs that increase QT: see www.azcert.org for an updated list (this stands for Arizona Centre for Education and Research on Therapeutics).

Jervell and Lange–Nielsen syndrome (JLNS)

This autosomal recessive condition is characterised by congenital profound bilateral sensorineural hearing loss and LQTS, with the corrected QT interval being greater than 500 ms (markedly prolonged, at 557 ± 65 ms). It is caused by an abnormality in a potassium channel, which is found in two places in the body; the stria vascularis of the cochlea, and the heart. It classically presents as a deaf child having syncopal episodes when stressed or frightened, or when exercising. The diagnosis requires the presence of two disease-causing mutations of the genes KCNQ1 or KCNE1, the only two genes known to be associated with JLNS. KCNQ1 and KCNE1 encode the alpha and beta subunit proteins (KvLQT1/minK) for the slow potassium current IKs of the cochlea and the heart. Mutations are found in KCNQ1 or KCNE1 in 94% of patients with JLNS; 90% of these are attributable to KCNQ1 and 10% to KCNE1. Mutations can be found in all coding exons. Around one third are compound heterozygotes.

Abnormal cardiac depolarisation and repolarisation can lead to prolonged QT interval and tachyarrhythmias, including VT, TdP and VF, which can cause syncope or sudden death: 50% of patients will have cardiac events before 3 years of age, triggered by emotions and exercise. Corrected QT prolongation in JLNS is associated with increased risk of sudden infant death syndrome (SIDS), and if untreated, more than half of the children with JLNS will die prior to 15 years of age. Up to 95% of people with JLNS have a cardiac event before adulthood. Although the sex ratio among patients with JLNS is equal, females have lower risk of SCD. Heterozygotes have normal hearing; in some heterozygotes, there is no QT prolongation; in others, there can be QT prolongation with fainting and risk of SCD, which is RWS as above. Only the genes KCNQ1 and KCNE1 are involved in both RWS and JLNS.

LQTS is also associated with other cardiac channelopathies: Brugada syndrome (see below), Andersen–Tawil syndrome (LQTS, episodic flaccid muscle paralysis, and dysmorphic features; potassium channel gene KCNJ2) and Timothy syndrome (LQTS with syndactyly, dysmorphic facial features and neurological disorders; average age of death from VT 2.5 years; calcium channel gene CACA1C; the recommended treatment is ICD). Acquired causes for LQTS include electrolyte abnormalities (hypokalaemia, hypocalcaemia and hypomagnesaemia), malnutrition, myocardial disease (cardiomyopathy, myocarditis) and drugs, including some vasodilators, tricyclic antidepressants, antihistamines and phenothiazines; the full list is at www.azcert.org, as mentioned above.

More than 50 mutations in four cardiac ion (sodium or potassium) channels on the myocyte have been delineated; medications implicated in causing LQTS affect these same channels. Symptomatic LQTS can be triggered by physical activity (e.g. swimming), intense or sudden emotions, or awakening, all of which cause adrenergic arousal. Syncopal events can be precipitated by competitive sports, amusement park rides, scary movies and jumping into cold water.

Any child (with cardiac disease in particular) who is due to commence any of the drugs known to trigger LQTS must have an ECG to measure the corrected QT interval (Bazett formula: QT (corrected) = QT/square root of the R–R interval; QT is measured from the start of the Q to the end of the T), which should be less than or equal to 0.46. If it is greater than this, avoid all drugs known to precipitate LQTS. Not all LQTS can be detected on a standard resting ECG; exercise ECG will unmask the 5% of those with the LQTS gene who have absent QT prolongation at rest.

As untreated LQTS has a mortality rate of around 50%, appropriate therapy should be commenced quickly once the diagnosis is made. Treatment options include, for the hearing impairment, cochlear implantation (CI), which does not interfere with bipolar pacemakers, but precautions still need be made during anaesthesia for this procedure because of the increased risk of arrhythmia. For the cardiac problem, the traditional first-line treatment has been beta blockers, which do reduce mortality, but unlike the situation with RWS, cardiac events in JLNS still can occur frequently despite beta blockade; the mortality rate for beta blockade treatment alone is 35% over 5 years, and 86% of patients will have a cardiac event.

Implantable cardioverter–defibrillators (ICDs) are advisable in those with a history of cardiac arrest, or high risk: corrected QT interval > 550 ms, syncope before 5 years old and male gender older than age 20 years with KCNQ1 mutation. Left cervicothoracic sympathetic ganglionectomy has been successful in some patients. Family members of those with JLNS should be trained in cardiopulmonary resuscitation (CPR), there should be availability of automated external defibrillators in the home, the school and, for older adolescents, the workplace; local emergency/ambulance services should be made aware of high-risk patients such as those with JLNS, and all patients should have a MedicAlert bracelet explaining their diagnosis.

LQTS should be sought/excluded in any child with breath-holding attacks, seizures precipitated by emotion or exertion, all initial afebrile seizures, unexplained syncope and congenital deafness.

Brugada syndrome

Described in 1992, this is an inherited cardiac disease causing ventricular tachyarrhythmias in patients with structurally normal hearts, presenting with syncope or cardiac arrest, and a strong family history of syncope or sudden death. It is inherited as autosomal dominant. There are eight types of Brugada syndrome listed in OMIM. For Brugada syndrome 1, the gene known to be associated is SCN5A, located at 3p21, which encodes the sodium channel protein type 5 subunit alpha in cardiac myocytes; there are over 160 known mutations in SCN5A. Mutations in SCN5A are found in 20–25% of patients with Brugada syndrome. It has a characteristic ECG pattern: right bundle branch block (RBBB) and ST elevation in V1 to V3; some patients with normal resting ECGs can have the classic changes induced by giving ajmaline, an antiarrhythmic medication. Implantable cardioverter–defibrillators (ICDs) can be placed in patients with a history of syncope or cardiac arrest, to prevent life-threatening arrhythmias; this is the only therapy known to be effective in these patients. Isoproterenol infusion can be used for electrical storms. Quinidine also has been used to prevent symptoms and resolve ECG features.

Brugada syndrome 2 is due to a mutation in the GPD1L gene; Brugada syndromes 3 and 4, phenotypes of which include a shortened QT on ECG, are caused by the mutations CACNA1C and CACNB2, respectively; Brugada syndrome 5 is caused by mutation in SCN1B; Brugada syndrome 6 is caused by mutation of the KCNE3 gene; Brugada syndrome 7 is due to mutation in the SCN3B gene; and Brugada 8 is caused by mutation in the HCN4 gene.

Drugs to avoid include Class 1C anti-arrhythmic drugs (including flecainide and propafenone) and Class 1A drugs (including procainamide and disopyramide). Drugs that unmask the Brugada ECG include tricyclic antidepressant drugs, alpha-adrenergic agonists, beta-adrenergic antagonists, first-generation antihistaminics (dimenhydrinate), anaesthetics and anti-psychotic drugs with sodium-blocking effects. Cocaine toxicity, vagotonic agents and being febrile, also unmask the Brugada ECG.

Brugada syndrome has three different ECG patterns. The diagnosis can be confirmed by finding: (a) Type 1 ECG (elevation of J point [junction between QRS complex and ST segment] at least 2 mm with a negative T wave and an ST segment that is of ‘coved’ type and gradually descending) in more than one right precordial lead (V1–V3), with or without administration of a sodium channel blocker (flecainide, pilsicainide, ajmaline or procainamide); and (b) at least one of documented VF, self-terminating polymorphic VT, a family history of SCD, ‘coved-type’ ECGs in family members, electrophysiological inducibility, syncope or nocturnal agonal respiration; and/or (c) a SCN5A mutation. Brugada syndrome should be considered with the following: Type 2 ECG (elevation of J point at least 2 mm, with a positive or biphasic T wave; the ST segment has a ‘saddle back’ pattern and is elevated at least 1 mm) in more than one right precordial lead, with conversion to Type 1 ECG following challenge with a sodium channel blocker; and Type 3 ECG (elevation of J point at least 2 mm, with a positive T wave; the ST segment has ‘saddle back’ configuration and is elevated < 1 mm) in more than one lead, with conversion to Type 1 ECG following challenge with a sodium channel blocker.

The parameter used for clinical decision-making is inducibility during electrophysiological study (EPS), which is highly predictive of subsequent events.

Brugada syndrome has a high risk of ventricular arrhythmias and sudden death. Males with easily induced arrhythmias and spontaneously abnormal ECGs have a 45% chance of an arrhythmic event at any time during life. Brugada syndrome usually manifests during adulthood, the mean age of sudden death being 40 years. It can present as sudden infant death syndrome (SIDS), or as sudden unexpected nocturnal death syndrome (SUNDS). Most patients who have Brugada syndrome diagnosed have inherited it from a parent; the proportion caused by de novo mutations is around 1% only; the family history may still be negative because of failure to recognise the condition.

Myocardial disease

Dilated cardiomyopathy (DCM)—familial dilated cardiomyopathy (FDC) and idiopathic dilated cardiomyopathy (IDC)

The most common form of cardiomyopathy, DCM, is characterised by left-ventricular enlargement, systolic dysfunction and reduced myocardial contraction force. It can present with Dysrhythmia, Congestive failure and Mural thrombus, leading to thromboembolic disease. The term ‘DCM’ can have a generic meaning (describing two features: left-ventricular enlargement and systolic dysfunction), and can be familial dilated cardiomyopathy (FDC), idiopathic dilated cardiomyopathy (IDC), which may in fact be familial in 20–50% of cases, or it may be secondary to therapeutic toxins (anthracyclines), radiation, inflammatory conditions, myocarditis, long-standing severe hypertension or thyroid disease. DCM (FDC) has been researched at the molecular level, identifying over 20 genes for autosomal dominant FDC, the commonest ones encoding the structural proteins of cardiac muscle: lamin-A/C, gene LMNA (7–8%); myosin 7, gene MYH7 (5–8%); sodium channel protein type 5 subunit alpha, gene SCN5A (2–4%), at least two genes for X-linked DCM, these genes encoding the proteins—dystrophin, gene DMD, and tafazzin, gene TAZ, and one gene for autosomal recessive inheritance DCM, encoding troponin I, cardiac muscle, gene TNNI3. Other genes are involved in metabolic causes, such as deficiencies of enzymes needed for myocardial fatty acid oxidation. First-degree relative screening should include the medical history, physical examination, an echocardiogram and ECG. Symptomatic DCM indicates late disease. Symptoms may be those of CCF (oedema, orthopnoea, paroxysmal dyspnoea), palpitations, chest pain, or exercise intolerance or syncope; signs include hypotension, weak peripheral pulses and hepatomegaly, with investigations showing cardiomegaly (CXR), arrhythmias (ECG), dilatation of the left ventricle and left atrium (echocardiography).

Treatment options include controlling CCF with antifailure therapy, including beta blockers (especially carvedilol) and ACE inhibitors, controlling arrhythmias with antiarrhythmics, consideration of pacemakers and implantable cardiac defibrillators, minimising the risk of thromboembolism with anticoagulants and antiplatelet drugs and, for those more refractive to treatment, a ventricular assist device or transplantation. Cardiac transplantation is still the definitive treatment for DCM refractory to medical, or device, therapy. Training in cardiopulmonary resuscitation is advisable for family members and caregivers.

Familial hypertrophic cardiomyopathy (HCM): also called hypertrophic obstructive cardiomyopathy (HOCM) and idiopathic hypertrophic subaortic stenosis (IHSS)

Inherited most often as an autosomal dominant trait, HCM penetrance is incomplete in early childhood, increasing with age. Over 900 mutations have been identified in the 12 genes that account for HCM, which encode various sarcomeric proteins, including, most commonly: myosin heavy chain, cardiac muscle beta isoform, gene MYH7 (40%); myosin-binding protein C cardiac-type, gene MYBPC3 (40%); troponin T, cardiac muscle, gene TNNT2 (5%); troponin I, cardiac muscle, gene TNNI3 (5%). Particular mutations determine prognostic factors, including risk of early death. HCM is occasionally transmitted as a mitochondrial disorder (i.e. maternally inherited).

Symptoms include failure to thrive, CCF, cyanosis, shortness of breath on exertion, dyspnoea, fatigue with exercise, chest pain, presyncope, syncope and palpitations. Signs include prominent left-ventricular apical impulse or lift, systolic murmur (increased by exercise, standing, straining; decreased by squatting), extra heart sounds (S3 and S4) and mid-diastolic rumble (mitral flow murmur with severe mitral regurgitation, with systolic anterior motion of the mitral valve). LVOT or intracavity obstruction may need provocative manoeuvres to detect their presence, such as the Valsalva manoeuvre, standing from squatting, and exercise. Investigations show cardiomegaly (CXR), right- and left-ventricular hypertrophy (RVH and LVH) in infants, LVH and abnormal Q waves in older children, LQTS in infants or older children, or arrhythmias (ECG), asymmetric septal hypertrophy, and concentric and apical hypertrophy (echocardiography or cardiac MRI). Other tests may include gated technetium-99m labelled blood pool scan (assess ejection fraction), thallium perfusion scan (regional perfusion abnormalities) and positron emission tomography (regional metabolic abnormalities).

In children under the age of 4, there is a differential diagnosis of: (a) inborn errors of metabolism (the main one being glycogen storage disease II [Pompe disease], which presents in the first few months of life); (b) malformation syndromes (the main one being NS; see above); and (c) neuromuscular disorders (the main one being Friedreich ataxia, FRDA, with slow-onset ataxia between 10 and 15 years, and diagnosed on molecular genetic testing of FXH). Other (rarer) secondary causes of HCM include Beckwith–Wiedemann syndrome, and mitochondrial diseases.

Treatment includes beta blockers (e.g. propranolol, atenolol) or calcium channel blockers (e.g. verapamil, nifedipine) for those who are symptomatic (note: verapamil excluded in infants under 12 months, or in those with major conduction disturbances), and consideration of the same treatment for asymptomatic children with a worrying family history. Disopyramide may be used if the other drugs are unsuccessful. Children with lethal, refractory arrhythmias may be treated with amiodarone.

If there is a high risk of cardiac arrest, or the patient is a survivor of cardiac arrest, then an implantable cardioverter–defibrillator (ICD) is recommended. Endocarditis prophylaxis is important. Resistant atrial fibrillation may warrant anticoagulation. Active sports participation is exceedingly unwise. It is important to avoid the following: competitive endurance training, heavy weight training, sprinting, dehydration, hypovolaemia, and medication that increases afterload (ACE inhibitors, ARBs) and other direct vasodilators.

Surgery is an option for failed medical therapy, to ease subaortic obstruction; the Morrow operation (myotomy/myectomy) can relieve symptoms and prolong life. Cardiac transplantation is a further option for high-risk patients. Around 5–10% of HCM progress to end-stage disease; without transplant, annual mortality is 11%.

Congestive cardiac failure (CCF)

CCF, irrespective of the cause, involves some form of cardiac injury that activates compensatory and deleterious pathways, which can cause chronic progressive deterioration that ultimately can hasten the demise of the patient. CCF is the most common cause for children with heart disease being prescribed medication, and accounts for at least half of paediatric referrals for heart transplantation. Around 40% of paediatric patients with cardiomyopathy develop heart failure to the degree that will be fatal without a transplant, and around 20% of children with structural heart disease will develop CCF. Symptoms may be feeding difficulties due to dyspnoea, getting tired easily and failure to thrive; signs may include mild to severe intercostal and subcostal recession, grunting, tachycardia, gallop rhythm (S3, S4) and hepatomegaly.

Principles/aspects of managing CCF can be listed as follows (mnemonic ASPECTS):

A. Afterload reduction: ACEIs, ARBs, brain natriuretic peptide (BNP), milrinone, nitrates

S. Sympathetic inhibition: beta blockers, BNP, digoxin

P. Preload reduction: BNP, diuretics

E. Enhanced contractility (inotropy): digoxin

C. Cardiac remodelling prevention: mineralocorticoid inhibitors (spironolactone)

T. Timely surgical repair of structural congenital heart disease

S. Systemic disease recognition and treatment (of pathology underlying CCF)

Angiotensin-converting enzyme (ACE) inhibitors (e.g. captopril) are very useful in lowering afterload and have been shown to decrease mortality in adults (but must be avoided in HCM, as above); they are usually started in hospital due to the risk of initial dose hypotension and the worsening of any unrecognised renovascular pathology. Diuretics (e.g. combined low-dose loop and thiazide diuretics) give rapid symptomatic relief; diuretics reduce preload, which prevents high cardiac filling pressures (which could lead to pulmonary oedema). Mineralocorticoid inhibitors (e.g. spironolactone) can help prevention of maladaptive cardiac remodelling and interstitial fibrosis. Digoxin is still widely used; it acts as an inotrope, but its use remains controversial and in adults it does not increase survival in CCF—indeed, there are no studies demonstrating its efficacy. Beta blockers (e.g. metoprolol, carvedilol) also are used increasingly in carefully graduated doses. Growth hormone has been used in a small number of patients (e.g. pre-transplant) and has been associated with improved indices on echocardiography, increased exercise capacity and decreased myocardial oxygen consumption. Nesiritide, which is a recombinant form of BNP, causes both diuresis and vasodilation, decreases both preload and afterload, inhibits the sympathetic nervous system, promotes cardiac myocyte survival and inhibits cardiac fibroblast activation; it shows promise as a third-line therapy, but studies in the paediatric age group are lacking at this stage.

There are surgical forms of circulatory support other than transplantation. External left-ventricular support devices and second-generation implantable devices have been developed, which provide prolonged mechanical unloading and can be used in myocarditis. These surgical support methods can act as a ‘bridge’ to transplantation, or a ‘bridge’ for biding time until the myocardium recovers in cases of myocarditis with acute cardiogenic shock. Advances in the technology of axial flow impeller pumps are producing smaller devices (e.g. the Jarvik 2000 impeller pump, smaller than a finger, but capable of a flow of 3 L/min). Another procedure for end-stage disease is partial left ventriculectomy and mitral valve replacement/repair (the Batista operation). This has been successful in children with DCM. The ultimate therapy for CCF refractory to medical treatment is cardiac transplantation.

Cardiac transplantation

Transplantation is now a well-established procedure for infants and children with severe congenital heart disease with ventricular failure (accounting for around two thirds of cases) or end-stage cardiomyopathies (around one third of cases), and survival rates continue to improve: 90% at 1 month, 85% at 1 year, 68–75% at 5 years, 58–65% at 10 years and 40% at 20 years. In the older population of children (beyond infancy), cardiomyopathies account for most transplantations: 55% of those aged 1–10 years, and 64% of those in adolescents. For transplantation to be considered, generally the life expectancy is below 1 or 2 years, and/or quality of life is very poor. Prognosis is worse for those under 1 year of age and those with assistive devices. Survivors of childhood cancer with cardiomyopathy due to anthracyclines represent a growing number of potential recipients, as do babies requiring primary transplantation for hypoplastic left-heart syndrome. A small percentage are retransplantations (around 3–5% of all paediatric transplants).

Indications for heart transplantation can be divided into two broad groups: life-saving indications and life-enhancing indications:

Life-saving: (CC,UU,RR): CCF with symptomatic ventricular dysfunction secondary to myocardial disease or palliated CHD; Complex CHD with failed surgical correction; Unresectable tumours; Unresectable ventricular diverticula; Rhythm disturbances: life-threatening (arrhythmias), resistant to therapy; Retransplantation (graft vasculopathy, ventricular dysfunction).

Life-enhancing: (CC,FF,II): CCF associated with pulmonary hypertension; Cardiomyopathy—restrictive, with poor survival overall; Fontan circulation with protein-losing enteropathy resistant to medical therapy; Fontan failing with decreased exercise tolerance, and declining quality of life; Inoperable AV valve or aortic regurgitation; Inoperable CHD with severe oxygen desaturation.

There are some fetal indications for listing on the transplant waiting list in North America. These include: hypoplastic left-heart syndrome, where transplantation is primary therapy; intractable arrhythmias; unresectable cardiac tumours; cardiomyopathies with poor ventricular function; right-atrial isomerism syndromes; and single-ventricle anatomy with risk factors for surgical palliation (severe atrioventricular valve regurgitation, decreased function). Candidates are listed from 35 weeks gestation and weight over 2.5 kg; if a donor heart becomes available, then patients are delivered by caesarean section, followed by immediate transplantation.

Transplant surgery may involve the biatrial technique, where there is anastomosis of donor and recipient aortas, pulmonary arteries and atrial cuffs; this can be associated with conduction disturbances, and a pacemaker is needed in 4–15% of patients; also this can cause higher thromboembolism rate, poorer atrial synchrony and AV valve regurgitation (due to atrial anatomy being altered). The other transplant technique is the bicaval approach, where the right atrium remains intact as the donor and recipient superior vena cava (SVC) and inferior vena cava (IVC) are anastomosed; this is associated with fewer of the above complications.

The major problem is finding suitable donors. The donor pool for infants under 12 months can include ABO-incompatible (ABO-I) transplants, as these have been shown to have equal long-term survival compared to ABO-compatible transplantations. Administration of blood products during and following ABO-I transplants must be done very carefully, to ensure there are no isohaemagglutinins against the donor or the recipient. For combined heart–lung transplantation (which is only indicated for severe pulmonary parenchymal or vascular disease with poor left-ventricular function, single ventricle anatomy, or a lesion requiring exceedingly complicated repair with excessive ischaemic time) the usual requirements are ABO and CMV compatibility plus donor–recipient chest size compatibility within 10%. The main immunosuppressive drugs used include the antiproliferatives (azathioprine [AZA], sirolimus or mycophenolate mofetil [MMF], which increasingly is replacing AZA in many centres), the calcineurin inhibitors (cyclosporin [CSA] or tacrolimus [TRL]) and steroids. Most centres have a triple immunosuppression protocol involving one agent from each group.

Allograft rejection occurs to a moderate or severe degree in most children, with the risk of rejection being highest in the first 6 months, and remains the most common cause of mortality in the first 3 years post-transplant. Risk factors for rejection are older age at transplant, CMV, gender mismatch or a previous episode of rejection. Rejection can be asymptomatic, but severe acute rejection can cause tiredness, poor appetite, nausea, poor feeding, abdominal pain, weight gain or fever. Haemodynamically significant rejection is associated with an increased mortality rate. However, there is no blood test proven to screen accurately for rejection; in most centres, endomyocardial biopsy is the diagnostic gold standard. Infections remain a significant cause of morbidity. Early infections (up to a month after transplant) are usually bacterial or fungal; intermediate (2–6 months after transplant) infections are often viral (e.g. Epstein–Barr virus [EBV], cytomegalovirus [CMV]); and late infections include viruses (EBV, varicella) and fungi (e.g. Aspergillus genus).

The commonest long-term side effects are related to immunosuppression:

• Coronary artery disease in up to 75% examined by intravascular ultrasound 5 years after transplant. Symptoms can include presyncope, syncope, exercise intolerance and chest pain (rare due to denervation of the transplanted heart). This form of chronic rejection is an accelerated graft vasculopathy that presents at a median of 6 years. To assess risk, coronary angiography can be done 1–2 yearly and, if positive, infers severe disease. Other imaging studies can be used: myocardial perfusion scanning, dobutamine stress echocardiography and MRI studies. Several agents are being investigated for prevention of vasculopathy, including calcium antagonists, ACEIs, vitamin E, statins, aspirin, MMF and rapamycin. Coronary artery disease may lead to need for retransplantation.

• Hypertension in up to 60% at 5 years; more in those on steroids and CSA; less with CSA alone; least with TRL alone. Aggressive treatment is required, usually with an ACE inhibitor or the calcium blocker diltiazem. For those with relevant congenital heart pathology, evaluation for residual pathology (e.g. residual coarctation) is required; check renal function yearly; nuclear scans may be needed to calculate the glomerular filtration rate (GFR).

• Neoplasia in 20%, most commonly lymphoproliferative diseases, at 6 months to 6 years after transplantation.

• Abnormal renal function in up to 25% at 5 years. With longer survival, a small number of patients are developing end-stage renal disease (ESRD) and then have a renal transplant; increased use of MMF and sirolimus (no renal toxicity) may allow decreased use of CSA and TRL and thus less nephrotoxicity.

• Osteoporosis probably occurs in 100%: steroids and calcineurin inhibitors decrease bone formation and increase bone destruction; steroids decrease calcium absorption. Supplemental calcium and vitamin D are recommended; protocols have been developed that include biphosphates, calcitonin and hormone replacement, although paediatric data is scant. Yearly bone density (DEXA) scanning is useful.

Other long-term issues include psychological issues (up to a third of children have behavioural problems at 5 years post-transplant—neurocognitive and neuropsychiatric support are important), non-compliance in adolescents and altered lifestyle requirements (need to get routine exercise 3–4 times a week, for at least 30 minutes, stop smoking, and maintain a heart-healthy diet, avoiding saturated fats and cholesterol).

Contraindications to transplantation are becoming fewer over the years. Currently (2010) the only contraindications are: (a) severe irreversible end organ damage or multisystem organ failure; (b) severe irreversible pulmonary hypertension; (c) active infection; (d) anatomical features that technically preclude transplant, such as severe hypoplasia of branch pulmonary arteries (as distal branch arteries are from the recipient and cannot be corrected with transplantation) and severe pulmonary vein stenosis or atresia (as the recipient veins are connected to the donor left atrium); (e) a severe or progressive non-cardiac condition with limited survival (mitochondrial disorders, untreatable metabolic disorders, Duchenne muscular dystrophy, cancer); and (f) psychological issues—non-compliance, smoking, drug abuse and psychiatric conditions.

There are some fetal indications for listing on the transplant waiting list. These include: hypoplastic left-heart syndrome, where transplantation is primary therapy; intractable arrhythmias; unresectable cardiac tumours; cardiomyopathies with poor ventricular function; right-atrial isomerism syndromes; and single-ventricle anatomy, with risk factors for surgical palliation (severe atrioventricular valve regurgitation, decreased function). Candidates are listed from 35 weeks gestation and weight over 2.5 kg; if a donor heart becomes available, then patients are delivered by caesarean section, followed by immediate transplantation.

Telemedicine

Advances in telecommunications technology, with the widespread introduction of integrated services digital network (ISDN) lines, allows transmission of echocardiogram images from peripheral to tertiary centres, with a paediatric cardiologist interpreting the transmitted images and guiding the performance of the scan to ensure that the best possible views are obtained. This approach has been used successfully in many countries. The defects that must be correctly diagnosed early include those causing cyanosis, obstructive lesions of the left and right heart, and total anomalous pulmonary venous drainage (TAPVD), the latter providing the greatest diagnostic difficulty. The other two lesions that can be difficult to diagnose are coarctation of the aorta (obtaining good aortic arch views can be challenging) and patent ductus arteriosus (and, if present, ascertaining how much it contributes clinically).

Cardiac imaging

Positron emission tomography (PET) scanning is being used to assess the cross-sectional functioning of the myocardium after significant cardiac insults related to coronary artery problems, such as in Kawasaki disease, corrective surgery for congenital heart disease (coronary occlusion can complicate the arterial switch procedure for transposition of the great arteries) and coronary arteriopathy seen in cardiac transplantation (here, there may be few clues; chest pain does not occur as the heart is denervated). Cardiac PET studies can assess regional substrate metabolism, chemical recognition (of receptors and enzymes) and regional blood flow. It can accurately differentiate between areas that can be reperfused (so-called stunned’ areas) and infarcted areas from irreversible ischaemia.

Short Case

The cardiovascular system

As one of the most common examination cases, a cardiac case is expected to be performed extremely well. A slick, complete examination, followed by a logical, relevant differential diagnosis and sensible interpretation of chest X-rays and electrocardiograms are all minimum requirements.

Introduce yourself. Stand back and give a brief general description of the child. Note any dysmorphic features (Down, Turner, Noonan, Williams, Marfan, Alagille syndromes) and general growth parameters (in particular, failure to thrive or short stature). Then fully expose the child’s chest. Look for any scars (so as not to miss a Blalock shunt, which may be associated with an absent radial pulse on that side; look for scars over the back, in the infrascapular region, for previous repair of coarctation of the aorta or of patent ductus arteriosus) or chest asymmetry. Pick up the child’s hands, check the fingernails for clubbing and splinter haemorrhages, and check the toenails. Feel the radial pulse, noting the rate, amplitude and character; lift the arm up to detect hyperdynamic pulsation (e.g. aortic incompetence). Note the respiratory rate at this stage (left-ventricular failure). Feel both radial pulses and femoral pulses: absent femoral pulses, with normal or increased brachial pulses, suggest coarctation (brachiofemoral delay is found only in adults with coarctation.) Next, ask to measure the blood pressure in both upper limbs. Usually, the examiners will give the values, but at other times you may be given a sphygmomanometer to measure it yourself. Check the jugular venous pressure (JVP) in older children, by sitting them at 45° in the standard manner.

Look at the conjunctivae for pallor and the sclera for icterus (haemolysis associated with artificial valves). Look at the tongue and state whether the patient is cyanosed; if uncertain, comment on the need to look again in natural daylight, if the room is artificially lit. Avoid saying ‘pink’ or ‘blue’: say ‘not cyanosed’ or ‘cyanosed’. Check the teeth for caries in view of the risk of subacute bacterial endocarditis (SBE). So far, the examination should have taken less than 2 minutes.

Now, turn your attention to the chest. If not already done, check for scars and asymmetry carefully. At this point, lie the child down on the examination bed. Look for the apex beat and then palpate for it. Describe the location (make a show of counting down the intercostal spaces) and the quality of the impulse. Beware of dextrocardia if the apex appears elusive. After the apex, feel the parasternal border and substernal region for heaves, and the suprasternal and supraclavicular regions for thrills, and feel over the pulmonary area for palpable closure of the pulmonary valve (i.e. ‘palpable S2’).

By the time auscultation is performed, a short list of possibilities should have been formulated, based on previous findings, by considering the following points as you proceed:

1. Cyanotic or acyanotic.

2. Heart failure or not heart failure.

3. Peripheral findings (pulses, blood pressure, JVP).

4. Praecordial findings.

Auscultation should commence at the apex, with the diaphragm of the stethoscope initially and then the bell (for diastolic murmurs). Listen at the apex, work across to, and up, the parasternal border, and listen over pulmonary and aortic areas. Listen to each component of the cardiac cycle carefully. Note the intensities of S1 and S2 and whether S2 splits normally with respiration. Listen for added sounds, in particular any ejection click, noting the point of maximal intensity, or any opening snap (mitral stenosis; rare) and then systolic and diastolic murmurs. Note radiation of any murmurs to axillae or carotids. Next, sit the child up and listen to any murmur’s variation with this change in position. Listen with the child in full expiration for the subtle early diastolic murmur of aortic incompetence.

Listen to the back for radiation of any murmurs and for any pulmonary adventitious sounds (inspiratory crackles with left-ventricular failure; variable findings with coexistent chest infection in Kartagener’s primary ciliary dysmotility syndrome). Lay the child down again and examine the abdomen for hepatomegaly (congestive cardiac failure), pulsatile liver (tricuspid incompetence) and splenomegaly (SBE). Then, feel for ankle oedema. Request the urinalysis for blood (SBE) and the temperature chart (SBE). If SBE does appear likely, request an ophthalmoscope to detect Roth spots.

Give a succinct differential diagnosis based on your clinical findings; only after this should you request the chest X-ray and ECG.

You do not have to give a specific diagnosis immediately; this is fraught with danger. If, for example, you are sure that a patient has valvular aortic stenosis, you should say so, but if there is any uncertainty, it is prudent to give as a diagnosis ‘left-ventricular outflow tract obstruction’ (LVOTO) and then proceed to delineate which of the various causes of LVOTO (supravalvular, valvular or subvalvular) is most likely and why. Supravalvular LVOTO has a thrill, valvular LVOTO has a click and a thrill, and subvalvular LVOTO has neither.

If you hear a murmur in the region of the pulmonary valve, the possibilities include a pulmonary flow murmur, an atrial septal defect (which is technically also a pulmonary flow murmur) or a right-ventricular outflow tract obstructive lesion; it is prudent to describe it initially as a ‘right-ventricular outflow tract’ (RVOT) murmur, and then delineate at which level it could be, if there are clues as to an obstructive lesion (supravalvular, valvular or subvalvular). If you hear a systolic ejection click, then you can be confident this is at the valvular level; if there is a thrill at the upper left sternal border, or in the suprasternal notch, then the lesion could be at a valvular level or above, the click differentiating the two.

Additional manoeuvres may be needed to clarify suspected diagnoses. The Valsalva manoeuvre is useful in identifying hypertrophic cardiomyopathy (HCM), as it increases the intensity of the murmur (via increased intrathoracic pressure, decreased venous return and hence decreased intracardiac volume and more severe LVOTO), and in mitral valve prolapse, where the murmur is also increased and the systolic click is heard earlier. Innocent systolic outflow tract murmurs decrease in intensity in response to the Valsalva manoeuvre.

Exercising the child is especially useful in bringing out a tricuspid diastolic murmur in an atrial septal defect (ASD; see Figure 6.10); this is most easily achieved by having the child do several sit-ups. In patients with ventricular septal defects (VSDs) and ASDs, the appearance of a mid-diastolic murmur suggests a pulmonary blood flow at least twice that of the systemic circulation, and in patients with mitral or tricuspid incompetence, such a murmur suggests at least a moderate degree of regurgitation.

With any findings strongly suggestive of a specific diagnosis, make a point of going beyond simple diagnosis of the said lesion, and be aware of clinical signs indicating the severity of that lesion. For example, with a ventricular septal defect, assess the size of the shunt, as outlined above; with pulmonary stenosis, assess the severity by the timing of the peak of the murmur, the associated presence or absence of a click, movement of S2 with respiration, and clinical signs of right-ventricular hypertrophy.

With an infant or fractious toddler, the approach is different, and the order may need to be completely rearranged. Distant observation is very important, noting size, colour, respiratory rate and perfusion. It is appropriate to tell the examiners that you are going to start with auscultation while the baby is quiet; if the baby does become restless, a breast or bottle may be a life saver. With a very uncooperative child, the key is to do what you can, while you can, without becoming angry or overtly frustrated. Your approach to this is just as important as your differential diagnosis or ECG interpretation.

One final point concerns correct coinage in cardiac cases. Do not use abbreviations when presenting your finding or in your discussion: do not say ‘VSD’, but say ‘ventricular septal defect’, and say ‘electrocardiogram’, not ‘ECG’.

Figure 6.8 shows the major points as outlined above. A more comprehensive listing of possible findings on cardiovascular examination is given in Table 6.1 (see also Figure 6.9 and Figure 6.7).

Figure 6.8 The cardiovascular system

Table 6.1 Additional information: possible findings on cardiovascular examination

General observations

Height

• Short (Down, Noonan, Turner; heart disease causing failure to thrive, e.g. Iarge atrioventricular canal)

• Tall (Marfan; check arm span if you suspect this)

Weight: failure to thrive (congenital rubella, severe heart disease, cyanosis or congestive cardiac failure) Head circumference: small (congenital rubella) Dysmorphic syndromes: Down, Noonan, Marfan, Turner, Williams, Alagille, neurofibromatosis type 1 Scars

• Median sternotomy (all open heart corrections)

• Lateral thoracotomy (e.g. coarctation repair, pulmonary artery banding, ligation of PDA or vascular ring, pulmonary artery reconstruction, shunts)

• Groin (cardiac catheters)

Chest asymmetry

• Left chest prominence (chronic right-ventricular hypertrophy)

• Right chest prominence (dextrocardia with chronic ventricular hypertrophy)

Respiratory rate: tachypnoea with left-ventricular hypertrophy Upper limbs Nails: check both hands and both feet

• Clubbing (cyanotic heart disease, SBE, suppurative lung disease—e.g. Kartagener): note any differential clubbing (e.g. clubbed toes, normal fingers in Eisenmenger syndrome with patent ductus)

• Splinter haemorrhages (SBE)

Pulses

• Rate, amplitude, character (lift arm to detect hyperdynamic pulsation of Al) and rhythm

• Radial (both sides, for radioradial delay)

• Brachial and femoral together (for brachiofemoral delay in older adolescents)

• Femorals (both sides): reduction of one femoral only is not due to coarctation, but to local trauma (cardiac catheter)

Blood pressure Both upper limbs All four limbs if any suggestion of coarctation Jugular venous pressure (sit child at 45°): elevated in right-ventricular failure

Figure 6.9 Idealized diagram of the temporal events of a cardiac cycle.

Behrman et al, 2007. Nelson Textbook of Paediatrics, 17th edition, Figure 415.3.

Figure 6.7 Four primary areas of auscultation.

Redrawn from; Pediatric Clinics of North America, Volume 45 No. 1 February 1998, p. 114, Figure 4.

Chest X-ray and electrocardiography

At the completion of the cardiac short case, it is customary to request the accompanying chest X-ray and electrocardiogram.

Chest X-ray (CXR)

When describing a CXR, first note the name and date, and then which side is marked right (the position of the gastric air bubble on the left can help unless there is complete situs inversus) to avoid the embarrassment of missing dextrocardia twice (once clinically and then again on the CXR). Then comment on the centering and penetration of the film, and the degree of inspiration. The cardiac diameter should be measured and compared to chest width at the level of the right hemidiaphragm (cardiothoracic ratio); normally this ratio is less than 50% (but up to 55–60% in neonates).

Next, the cardiac contour can be assessed, particularly for the size of the pulmonary artery and the position of the aortic arch. Then, the lung fields should be evaluated, with particular emphasis on pulmonary vascularity (see below). Finally, the bony structures are assessed, especially for rib notching in children with possible coarctation.

In cyanosed children, check whether pulmonary vascularity is increased or decreased. Note however, that most of these conditions (such as the ‘increased pulmonary vascularity’ list below) will not be seen in the exam context, as they pertain only to the early neonatal period and will all be subject to early repair. Some of the decreased vascularity list may be seen in the exam context, such as pulmonary atresia with multiple aorto-pulmonary collaterals (MAPCs), although this is uncommon.

Increased pulmonary vascularity occurs in the following:

1. Truncus arteriosus (Figure 6.5).

2. Total anomalous pulmonary venous drainage (TAPVD).

3. One condition of ‘textbook interest’, rarely seen outside the neonatal period nowadays, which is transposition of the great arteries (TGA).

Figure 6.5 Physiology of truncus arteriosus.

Circled numbers represent oxygen saturation values. Right atrial (mixed venous) oxygen saturation is decreased secondary to systemic hypoxemia. Desaturated blood enters the right atrium, flows through the tricuspid valve into the right ventricle, and is ejected into the truncus. Saturated blood returning from the left atrium enters the left ventricle and is also ejected into the truncus. The common aortopulmonary trunk gives rise to the ascending aorta and to the main or branch pulmonary arteries. Oxygen saturation in the aorta and pulmonary arteries is usually the same (definition of a total mixing lesion). As pulmonary vascular resistance decreases over the first few weeks of life, pulmonary blood flow increases dramatically and mild cyanosis and congestive heart failure result. Behrman et al, 2007. Nelson Textbook of Paediatrics, 17th edition, Figure 424.6.

Decreased pulmonary vascularity occurs in the following:

1. Pulmonary atresia with MAPCs (Figure 6.14).

2. Tricuspid atresia (Figure 6.15).

3. Ebstein’s anomaly (Figure 6.13).

4. Tetralogy of Fallot: 25% of these have a right-sided aortic arch.

5. Another cause is critical pulmonary stenosis associated with a right-to-left shunt in the neonatal period, but this again is more of ‘textbook interest’.

Figure 6.14 Physiology of pulmonary atresia with an intact ventricular septum.

Circled numbers represent oxygen saturation values. Right atrial (mixed venous) oxygen saturation is decreased secondary to systemic hypoxemia. A small amount of the blood entering the right atrium may cross the tricuspid valve, which is often stenotic as well. The right-ventricular cavity is hypertrophied and may be hypoplastic. No outlet from the right ventricle exists because of the atretic pulmonary valve; thus, any blood entering the right ventricle returns to the right atrium via tricuspid regurgitation. Most of the desaturated blood shunts right to left via the foramen ovale into the left atrium, where it mixes with fully saturated blood returning from the lungs. The only source of pulmonary blood flow is via the patent ductus arteriosus. Aortic and pulmonary arterial oxygen saturation will be identical (definition of a total mixing lesion). Behrman et al, 2007. Nelson Textbook of Paediatrics, 17th edition, Figure 423.6.

Figure 6.15 Physiology of tricuspid atresia with normally related great vessels.

Circled numbers represent oxygen saturation values. Right atrial (mixed venous) oxygen saturation is decreased secondary to systemic hypoxemia. The tricuspid valve is non-patent, and the right ventricle may manifest varying degrees of hypoplasia. The only outlet from the right atrium involves shunting right to left across an atrial septal defect or patent foramen ovale to the left atrium. There, desaturated blood mixes with saturated pulmonary venous return. Blood enters the left ventricle and is ejected either through the aorta or via a ventricular septal defect (VSD) into the right ventricle. In this example, some pulmonary blood flow is derived from the right ventricle, the rest from a patent ductus arteriosus (PDA). In patients with tricuspid atresia, the PDA may close or the VSD may grow smaller and result in a marked decrease in systemic oxygen saturation. Behrman et al, 2007. Nelson Textbook of Paediatrics, 17th edition, Figure 423.7.

Figure 6.13 The physiology of the Ebstein anomaly of the tricuspid valve.

Circled numbers represent oxygen saturation values. Inferior displacement of the tricuspid valve leaflets into the right ventricle has resulted in a thin-walled, low-pressure ‘atrialized’ segment of right ventricle. The tricuspid valve is grossly insufficient (clear arrow). Right atrial blood flow is shunted right to left across an atrial septal defect or patent foramen ovale into the left atrium. Some blood may cross the right-ventricular outflow tract and enter the pulmonary artery; however, in severe cases, the right ventricle may generate insufficient force to open the pulmonary valve, and ‘functional pulmonary atresia’ results. In the left atrium, desaturated blood mixes with saturated pulmonary venous return. Blood enters the left ventricle and is ejected via the aorta. In this example, some pulmonary blood flow is derived from the right ventricle, the rest from a patent ductus arteriosus (PDA). Severe cyanosis will develop in neonates with a severe Ebstein anomaly when the PDA closes. Behrman et al, 2007. Nelson Textbook of Paediatrics, 17th edition, Figure 423.10.

Electrocardiography

Start by determining the rate (roughly—do not waste time), the rhythm and then the axis. Next, systematically look at the P waves, the P–R interval, then the QRS complexes, the S–T interval and finally the T waves. Several patterns give important clues to the diagnosis. The age of the child must always be taken into consideration. The following lists outline several important points regarding age-related changes and clues to certain diagnoses.

Axis

1. Birth: +60° to +180°.

2. 1 year: +10° to +100°.

3. 10 years: +30° to +90°.

Right-axis deviation (RAD)—that is, an axis at +90° to +180° (after infancy)—is often associated with right-ventricular hypertrophy, whereas left-axis deviation (LAD) has numerous causes, including atrioventricular canal (Figure 6.11), tricuspid atresia and conduction anomalies.

Figure 6.11 Physiology of atrioventricular septal defect (AVSD).

Circled numbers represent oxygen saturation values. The numbers next to the arrows represent volumes of blood flow (in L/min/m²). This illustration shows a hypothetical patient with a pulmonary-to-systemic blood flow ratio (Qp:Qs) of 3:1. Desaturated blood enters the right atrium from the vena cavae at a volume of 3 L/min/m² and mixes with 3 L of fully saturated blood shunting left to right across the atrial septal defect; the result is an increase in oxygen saturation in the right atrium. Six litres of blood flows through the right side of the common AV valve, joined by an additional 3 L of saturated blood shunting left to right at the ventricular level, further increasing oxygen saturation in the right ventricle. The full 9 L flows across the right-ventricular outflow tract into the lungs. Nine litres returns to the left atrium, with 3 L shunting left to right across the defect and 6 L crossing the left side of the common AV valve and causing a mid-diastolic flow rumble. Three litres of this volume shunts left to right across the VSD, and 3 L is ejected into the ascending aorta (normal cardiac output). Behrman et al, 2007. Nelson Textbook of Paediatrics, 17th edition, Figure 419.2.

Specific diagnosis by ECG

Although a pathophysiological approach is, of course, preferable to a mnemonic or list in cardiology, ECGs do lend themselves to the latter. Table 6.2 is one such list, but rather than rote-learning this, the candidate should endeavour to understand the pathophysiology and always consider the ECG in the context of the clinical findings.

Table 6.2 Electrocardiographic findings and associated pathologies

If the finding is	Think of
Prolonged P–R interval	Endocardial cushion defect
	Ebstein anomaly
	Acute rheumatic fever
	Congenital block (maternal SLE)
Partial RBBB
with LAD	Ostium primum ASD
with RAD	Ostium secundum ASD
with RAH, delta waves	Ebstein anomaly
Complete RBBB	Post-ventriculotomy
LAD	Endocardial cushion defect
	Tricuspid atresia
	Hypertrophic cardiomyopathy
	Inlet VSD
RAH	Ebstein anomaly
without RVH	Tricuspid atresia (LAD)
	Pulmonary atresia with intact septum
with axis over 90°	Truncus arteriosus
	Tetralogy with large VSD
Deep Q waves	Hypertrophic cardiomyopathy
	Transposition of great arteries
	Anomalous left coronary artery

ASD = atrial septal defect; LAD = left axis deviation; RAD = right axis deviation; RAH = right atrial hypertrophy; RVH = right-ventricular hypertrophy; VSD = ventricular septal defect.