Expanding the phenotype of Bruck syndrome: Severe limb deformity, arthrogryposis, congenital cardiac disease and pulmonary hemorrhage.

Bruck syndrome is a rare collagen disorder with autosomal recessive inheritance caused by pathogenic variants in either FKBP10 or PLOD2 genes. It is characterized by bone fragility and fractures similar in severity and variability to osteogenesis-imperfecta as well as congenital joint contractures. This article describes an infant with a homozygous (partial) gene deletion of PLOD2 that includes the start codon and would be expected to lead to nonfunctional protein product. The infant had a severe phenotype of Bruck syndrome and is the only reported case of Bruck syndrome with congenital cardiac disease (triscuspid valve dysplasia with severe regurgitation, mitral valve prolapses with moderate regurgitation, and pulmonary hypertension) and pulmonary hemorrhage. We hypothesize that the additional feature of congenital cardiac disease in this case was due to the underlying defect in type I collagen, and that the pulmonary hemorrhage was multifactorial, with underlying vessel fragility, rib fractures, and high pulmonary pressures likely to be major contributing factors. Management was largely supportive with the use of bisphosphonates to assist in pain management. Care was complicated by comorbid cardiopulmonary compromise, limited evidence-base guiding care, and difficulties in discussing end-of-life care.

Bruck Syndrome: Beyond the Obvious.

INTRODUCTION: Bruck syndrome is a rare autosomal recessive disease characterized by multiple joint contractures, bone fragility, and fractures. Two genes have been associated with Bruck syndrome, FKBP10 and PLOD2, though they are phenotypically indistinguishable. CASE PRESENTATION: We present a prenatally diagnosed case of Bruck syndrome in a young multiparous woman, with no notable personal, family or obstetric history. A 12-week ultrasound raised the suspicion of short long bones, subsequently confirmed at 16 weeks. In addition, bilateral fixed flexion of the elbow, wrist, and knee joints as well as talipes was observed. Chromosomal SNP microarray analysis (0.2 Mb) detected a homozygous deletion at chromosome 3, band q24, involving a part of PLOD2 to a part of PLSCR4. At mid-trimester morphology, bilateral intrauterine fractures of the humerus and femur were evident. In the late third trimester, a fetal echocardiogram noted enlargement of the right heart with severe tricuspid regurgitation in combination with pulmonary insufficiency and a restrictive arterial duct. The potential risk of premature closure of the ductus arteriosus near term led to delivery by emergency caesarean section. CONCLUSION: To our knowledge, this is the first case of Bruck syndrome prenatally confirmed by chromosomal microarray analysis and the second reported case with an extra-skeletal abnormality. This case highlights the importance of comprehensive fetal morphological assessment during pregnancy as diagnosis of an additional abnormality has the potential to impact both management and prognosis.

Double drainage of total anomalous pulmonary venous connection: A rare variant of mixed total anomalous pulmonary venous connection.

Total Anomalous Pulmonary Venous Connection (TAPVC) is frequently classified based on the system proposed by Craig, Darling and Rothney. Occasionally variants are reported which do not fit into these classic forms. One such variant is the double drainage of TAPVC where the confluence has connections at two different levels. We report two infants with a double drainage pattern of TAPVC.

Myocardial Dimensions in Children With Hypertrophic Cardiomyopathy: A Comparison Between Echocardiography and Cardiac Magnetic Resonance Imaging.

BACKGROUND: The primary mode of imaging in hypertrophic cardiomyopathy (HCM) is transthoracic echocardiography (TTE). However, in adults inadequate acoustic windows lead to poor quantification of myocardial thickness compared with cardiac magnetic resonance (CMR) imaging. In comparison, children have better acoustic windows and TTE measurements of wall thickness might be more accurate. The aim of this study was to assess the performance of TTE compared with CMR for the assessment of myocardial thickness in children with HCM. METHODS: Nineteen children (median age, 12.7 years; range, 8.4-18.4 years) with known HCM were studied using TTE and CMR imaging on the same day. The left ventricle was measured off-line using the standard 16-segment model. RESULTS: With CMR imaging 304 (19 × 16) segments were analyzable whereas only 263 were analyzable using echocardiography. Wall thickness measurements according to TTE were greater than those according to CMR imaging in the basal anterolateral, midventricular anterior and anterolateral and apical inferior, lateral and septal segments and smaller for the midventricular inferior and inferoseptal segments. Reproducibility of CMR and TTE measurements was assessed using the intraclass correlation coefficient (ICC). CMR measurements showed excellent intrareader (ICC, 0.929-0.991) and moderate inter-reader (ICC range, 0.512-0.991) reproducibility. TTE measurements revealed moderate intrareader (ICC, 0.575-0.942) and poor inter-reader (ICC range, -1.02 to 0.939) reproducibility. CONCLUSIONS: Echocardiography incompletely assesses circumferential myocardial thickness in a proportion of pediatric patients with HCM. Echocardiography under- and overestimates maximum wall thickness compared with CMR, depending on the location. Measurements using CMR are more reproducible than those obtained using echocardiography.

Clinical Characteristics and Outcomes of Cardiomyopathy in Barth Syndrome: The UK Experience.

Barth syndrome (BTHS) is an X-linked disorder characterised by cardiomyopathy, neutropenia, skeletal myopathy and growth delay. This study describes the UK national clinical experience and outcome of cardiomyopathy in BTHS. The clinical course and echocardiographic changes of all patients with BTHS in the UK were reviewed from 2004 to 2014. In addition, strain analysis using 2D speckle tracking echocardiography was performed to further assess left ventricular function in the most recent follow-up. At last follow-up, 22 of 27 patients were alive with a median age of 12.6 (2.0-23.8) years; seven underwent cardiac transplantation at a median age of 2 (0.33-3.6) years, and five died (18.5%) at a median age of 1.8 (0.02-4.22) years. All deaths were related to cardiomyopathy or its management. Left ventricular diastolic dimension and systolic function measured by fractional shortening tended to normalise and stabilise after the first 3 years of life in the majority of patients. However, patients with BTHS (n = 16) had statistically significant reduction in global longitudinal and circumferential strain compared to controls (n = 18), (p < 0.001), despite apparent normal conventional measures of function. There was also reduced or reversed apical rotation and reduced left ventricular twist. Sustained ventricular arrhythmia was not seen at follow-up. Cardiac phenotype in BTHS is variable; however, longer-term outcome in our cohort suggests good prognosis after the first 5 years of life. Most patients appeared to have recovered near normal cardiac function by conventional echocardiographic measures, but strain analysis showed abnormal myocardial deformation and rotational mechanics.

The relationship between biventricular myocardial performance and metabolic parameters during incremental exercise and recovery in healthy adolescents.

Background left ventricular (LV) and right ventricular (RV) myocardial reserve during exercise in adolescents has not been directly characterized. The aim of this study was to quantify myocardial performance response to exercise by using two-dimensional (2-D) speckle tracking echocardiography and describe the relationship between myocardial reserve, respiratory, and metabolic exercise parameters. A total of 23 healthy boys and girls (mean age 13.2 ± 2.7 yr; stature 159.1 ± 16.4 cm; body mass 49.5 ± 16.6 kg; BSA 1.47 ± 0.33 m(2)) completed an incremental cardiopulmonary exercise test (25 W · 3 min increments) with simultaneous acquisition of 2-D transthoracic echocardiography at rest, each exercise stage up to 100 W, and in recovery at 2 min and 10 min. Two-dimensional LV (LV Sl) and RV (RV Sl) longitudinal strain and LV circumferential strain (LV Sc) were analyzed to define the relationship between myocardial performance reserve and metabolic exercise parameters. Participants achieved a peak oxygen uptake (V̇o 2peak) of 40.6 ± 8.9 ml · kg(-1) · min(-1) and a work rate of 154 ± 42 W. LV Sl and LV Sc and RV Sl increased significantly across work rates (P < 0.05). LV Sl during exercise was significantly correlated to resting strain, V̇o 2peak, oxygen pulse, and work rate (0.530 ≤ r ≤ 0.784, P < 0.05). This study identifies a positive and moderate relationship between LV and RV myocardial performance and metabolic parameters during exercise by using a novel methodology. Relationships detected present novel data directly describing myocardial adaptation at different stages of exercise and recovery that in the future can help directly assess cardiac reserve in patients with cardiac pathology.

Interrupted aortic arch with retrograde subclavian perfusion.

Type B interrupted aortic arch results in the left subclavian artery being perfused by a patent ductus arteriosus and antegrade flow is usually seen in the left subclavian artery. We describe a case of retrograde perfusion of the left subclavian artery through the circle of Willis in the presence of interrupted aortic arch type B and a restrictive patent ductus arteriosus. This is similar to subclavian steal syndrome when the perfusion pressure from the cerebral circuit is greater than that from the left subclavian artery. Early recognition of this phenomenon may alter management by indicating restriction at ductal level. This case highlights the need for a comprehensive review of both ventricular systolic function and ductal haemodynamics when retrograde flow is seen in the subclavian artery.

Long-term clinical experience with Amplatzer Ductal Occluder II for closure of the persistent arterial duct in children.

OBJECTIVES: To describe the long-term clinical experience and follow-up with the Amplatzer Ductal Occluder II (ADO II) in children. METHODS: All patients undergoing attempted transcatheter closure of patent arterial duct (PDA) with the ADO II were included. Data collected included demographic, clinical, and echocardiographic parameters. RESULTS: From March 2008 until March 2013, 62 patients with a median age of 1.2 years (range 0.43-11.1 years) and median weight of 9 kg (range 4.7-31.4 kg) underwent the procedure. The median measurement for minimal ductal diameter was 2.7 mm (range 1.3-5 mm). An ADO II was implanted in 60 patients (96.8%). Two patients had significant residual shunting following deployment of the ADO II and underwent closure with the Amplatzer ductal occluder I (ADO I) during the same procedure. In six patients, the initial ADO II was unsatisfactory, and after recapture a different size ADO II was deployed. Device embolization of the ADO II to the pulmonary artery occurred in 6.7% of patients. Of these, one underwent surgical closure and three were closed with an ADO I. Complete occlusion on echocardiography was noted prior to discharge in 87.5% of the deployed occluders and 100% at first follow-up. Five year follow-up (n = 25) revealed a 100% occlusion rate. There were three cases of persistent mild left pulmonary artery stenosis at long-term follow-up. CONCLUSIONS: The ADO II is effective for occlusion of PDA with variable anatomy from either arterial or venous approaches with a low profile delivery system. Stable occluder position is highly dependent on accurate device sizing, good quality imaging to visualize device configuration after deployment and operator experience.

Early changes in apical rotation in genotype positive children with hypertrophic cardiomyopathy mutations without hypertrophic changes on two-dimensional imaging.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is the most common form of inherited cardiomyopathy. Echocardiography is the mainstay of screening and disease surveillance, and genetic testing has identified a carrier population without hypertrophy. The aim of this study was to investigate whether changes in left ventricular (LV) function are detectable before the advent of hypertrophy. METHODS: Fourteen children with genotype-positive, phenotype-negative HCM were identified (12 male; median age, 9.14 years; range, 1.91-15.9 years; median weight, 34.6 kg; range, 15-92.1 kg) and compared with age-matched and sex-matched healthy controls. All children underwent full echocardiographic studies using an extensive functional protocol, including two-dimensional dimensions, Doppler tissue imaging, and two-dimensional speckle-tracking echocardiography. RESULTS: There were no differences in LV wall thickness, chamber dimensions, length, and shortening fraction between the groups. Doppler tissue imaging in children with HCM demonstrated mildly reduced septal velocities, notably A' (5.9 cm/sec [range, 4-8.9 cm/sec] vs 6.7 cm/sec [range, 5.2-9.5 cm/sec]; P = .009). Circumferential and longitudinal strain was similar between groups. Mean apical circumferential deformation was increased in the HCM group (-24.6 ± 3.8% vs -22.2 ± 2.5%, P = .04). There were significant increases in basal and apical rotation and LV twist in children with HCM, most marked at the apex (11.7 ± 4.4° vs 5.3 ± 2.5°, P = .0001). On receiver operating characteristic curve analysis, apical rotation > 7° conferred 83% sensitivity and 82% specificity for predicting HCM (area under the curve, 0.919; P = .0001). CONCLUSIONS: Increased LV rotation and twist are present in children with genotype-positive, phenotype-negative HCM. Apical rotation on speckle-tracking echocardiography provides good sensitivity and specificity for the prediction of gene-positive HCM and may be a clinically useful early marker of HCM before the onset of hypertrophy.

Fetal circulation in left-sided congenital heart disease measured by cardiovascular magnetic resonance: a case-control study.

BACKGROUND: The distribution of blood flow in fetuses with congenital heart disease (CHD) is likely to influence fetal growth, organ development, and postnatal outcome, but has previously been difficult to study. We present the first measurements of the distribution of the fetal circulation in left-sided CHD made using phase contrast cardiac magnetic resonance (CMR). METHODS: Twenty-two fetuses with suspected left-sided CHD and twelve normal controls underwent fetal CMR and echocardiography at a mean of 35 weeks gestation (range 30-39 weeks). RESULTS: Fetuses with left-sided CHD had a mean combined ventricular output 19% lower than normal controls (p < 0.01). In fetuses with left-sided CHD with pulmonary venous obstruction, pulmonary blood flow was significantly lower than in those with left-sided CHD without pulmonary venous obstruction (p < 0.01). All three fetuses with pulmonary venous obstruction had pulmonary lymphangectasia by fetal CMR and postnatal histology. Fetuses with small but apex forming left ventricles with left ventricular outflow tract or aortic arch obstruction had reduced ascending aortic and foramen ovale flow compared with normals (p < 0.01). Fetuses with left-sided CHD had more variable superior vena caval flows than normal controls (p < 0.05). Six fetuses with CHD had brain weights at or below the 5th centile for gestational age, while none of the fetuses in the normal control group had brain weights below the 25th centile. CONCLUSIONS: Measurement of the distribution of the fetal circulation in late gestation left-sided CHD is feasible with CMR. We demonstrated links between fetal blood flow distribution and postnatal course, and examined the relationship between fetal hemodynamics and lung and brain development. CMR enhances our understanding of pathophysiology of the fetal circulation and, with more experience, may help with the planning of perinatal management and fetal counselling.

Speckle tracking echocardiography in pediatric and congenital heart disease.

Assessment of myocardial strain using speckle tracking echocardiography is an emerging echocardiographic technique that is increasingly used in the diagnosis and management of acquired heart disease in adults. In pediatric heart disease, this is still mainly considered as a research tool as the application of this technology has been slowed by the lack of vendor-independent technology and of normative data across the different age ranges. We believe that the technology has potential applications for the early detection of myocardial dysfunction, the quantification of ventricular function in congenital heart disease, and the detection of dyssynchrony.

Patent arterial duct.

Patent arterial duct (PAD) is a congenital heart abnormality defined as persistent patency in term infants older than three months. Isolated PAD is found in around 1 in 2000 full term infants. A higher prevalence is found in preterm infants, especially those with low birth weight. The female to male ratio is 2:1. Most patients are asymptomatic when the duct is small. With a moderate-to-large duct, a characteristic continuous heart murmur (loudest in the left upper chest or infraclavicular area) is typical. The precordium may be hyperactive and peripheral pulses are bounding with a wide pulse pressure. Tachycardia, exertional dyspnoea, laboured breathing, fatigue or poor growth are common. Large shunts may lead to failure to thrive, recurrent infection of the upper respiratory tract and congestive heart failure. In the majority of cases of PAD there is no identifiable cause. Persistence of the duct is associated with chromosomal aberrations, asphyxia at birth, birth at high altitude and congenital rubella. Occasional cases are associated with specific genetic defects (trisomy 21 and 18, and the Rubinstein-Taybi and CHARGE syndromes). Familial occurrence of PAD is uncommon and the usual mechanism of inheritance is considered to be polygenic with a recurrence risk of 3%. Rare families with isolated PAD have been described in which the mode of inheritance appears to be dominant or recessive. Familial incidence of PAD has also been linked to Char syndrome, familial thoracic aortic aneurysm/dissection associated with patent arterial duct, and familial patent arterial duct and bicuspid aortic valve associated with hand abnormalities. Diagnosis is based on clinical examination and confirmed with transthoracic echocardiography. Assessment of ductal blood flow can be made using colour flow mapping and pulsed wave Doppler. Antenatal diagnosis is not possible, as PAD is a normal structure during antenatal life. Conditions with signs and symptoms of pulmonary overcirculation secondary to a left-to-right shunt must be excluded. Coronary, systemic and pulmonary arteriovenous fistula, peripheral pulmonary stenosis and ventricular septal defect with aortic regurgitation and collateral vessels must be differentiated from PAD on echocardiogram. In preterm infants with symptomatic heart failure secondary to PAD, treatment may be achieved by surgical ligation or with medical therapy blocking prostaglandin synthesis (indomethacin or ibuprofen). Transcatheter closure of the duct is usually indicated in older children. PAD in preterm and low birth weight infants is associated with significant co-morbidity and mortality due to haemodynamic instability. Asymptomatic patients with a small duct have a normal vital prognosis but have a lifetime risk of endocarditis. Patients with moderate-to-large ducts with significant haemodynamic alterations may develop irreversible changes to pulmonary vascularity and pulmonary hypertension.

Early clinical experience with the new Amplatzer Ductal Occluder II for closure of the persistent arterial duct.

OBJECTIVES: To describe the early single-center clinical experience with the Amplatzer Ductal Occluder II (ADO II). METHODS: All patients undergoing attempted transcatheter closure of persistent arterial duct (PDA) with the ADO II were included. Data collected included demographic, clinical, and echocardiographic parameters. RESULTS: From March until September 2008, 29 procedures were undertaken in 27 patients (21 female). Median age was 1.4 years (range 0.4-76 years) with median weight 9.4 kg (range 4.7-108 kg). A transarterial approach was used in 2 patients. The median minimum ductal diameter was 2.7 mm (range 1.7-5). ADO II was released in 25 patients (92.5%). Two patients had significant residual shunting following deployment of ADO II and underwent closure with Amplatzer ductal occluder (ADO I). Postprocedural echocardiography identified one occluder had changed position with development of a significant leak and one occluder had embolized to the left pulmonary artery. Both occluders were retrieved successfully at a second catheter procedure. Complete occlusion was noted predischarge in 22 of the remaining 23 occluders (96%). One patient had mild flow acceleration in the left pulmonary artery which has resolved. CONCLUSIONS: The ADO II is highly effective at providing rapid occlusion of morphologically varied PDAs. Occluder design allows closure with arterial or venous approach and delivery with 4 or 5 F delivery catheters. Stable occluder position is dependent on correct positioning of both aortic and pulmonary discs. A larger range of sizes and configurations of this occluder may be required to successfully occlude all ductal sizes and morphologies.