Treatments affecting splenic function as a risk factor for valvular heart disease in Childhood Cancer Survivors: A DCCSS-LATER study.

PURPOSE: Splenectomy might be a risk factor for valvular heart disease (VHD) in adult Hodgkin lymphoma survivors. As this risk is still unclear for childhood cancer survivors (CCS), the aim of this study is to evaluate the association between treatments affecting splenic function (splenectomy and radiotherapy involving the spleen) and VHD in CCS. METHODS: CCS were enrolled from the DCCSS-LATER cohort, consisting of 6,165 five-year CCS diagnosed between 1963 and 2002. Symptomatic VHD, defined as symptoms combined with a diagnostic test indicating VHD, was assessed from questionnaires and validated using medical records. Differences in the cumulative incidence of VHD between CCS who received treatments affecting splenic function and CCS who did not were assessed using the Gray test. Risk factors were analyzed in a multivariable Cox proportional hazards model. RESULTS: The study population consisted of 5,286 CCS, with a median follow-up of 22 years (5-50 years), of whom 59 (1.1%) had a splenectomy and 489 (9.2%) radiotherapy involving the spleen. VHD was present in 21 CCS (0.4%). The cumulative incidence of VHD at the age of 40 years was significantly higher in CCS who received treatments affecting splenic function (2.7%, 95% confidence interval (CI) 0.4%-4.9%) compared with CCS without (0.4%, 95% CI 0.1%-0.7%) (Gray's test, p = 0.003). Splenectomy was significantly associated with VHD in a multivariable analysis (hazard ratio 8.6, 95% CI 3.1-24.1). CONCLUSIONS AND IMPLICATIONS: Splenectomy was associated with VHD. Future research is needed to determine if CCS who had a splenectomy as part of cancer treatment might benefit from screening for VHD.

Comprehensive Evaluation of Pediatric Patients with Ebstein Anomaly Requires Both Echocardiography and Cardiac Magnetic Resonance Imaging.

With the trend towards childhood surgery in patients with Ebstein anomaly (EA), thorough imaging is crucial for patient selection. This study aimed to assess biventricular function by echocardiography and cardiac magnetic resonance (CMR) and compare EA severity classifications. Twenty-three patients (8-17 years) underwent echocardiography and CMR. Echocardiographic parameters included tricuspid annular plane systolic excursions (TAPSE), fractional area change of the functional right ventricle (fRV-FAC), fRV free wall peak systolic myocardial velocity (fRVs'), and tricuspid regurgitation (TR). End-diastolic and end-systolic volume (EDV resp. ESV), fRV- and LV ejection fraction (EF) and TR were obtained by CMR. EA severity classifications included displacement index, Celermajer index and the total-right/left-volume index. Median fRV-FAC was 38% (IQR 33-42). TAPSE and fRVs' were reduced in 39% and 75% of the patients, respectively. Echocardiographic TR was visually graded as mild, moderate, or severe in nine, six and eight patients, respectively. By CMR, median fRVEF was 49% (IQR 36-58) and TR was graded as mild, moderate, or severe in nine, twelve and two patients, respectively. In 70% of cases, fRV-EDV was higher than LV-EDV. LVEF was decreased in 17 cases (74%). There was excellent correlation between echocardiography-derived fRV-FAC and CMR-derived fRVEF (rho = 0.812, p < 0.001). While echocardiography is a versatile tool in the complex geometry of the Ebstein heart, it has limitations. CMR offers a total overview and has the advantage of reliable volume assessment of both ventricles. Comprehensive evaluation of pediatric patients with EA may therefore require a synergistic implementation of echocardiography and CMR.

Myocardial Function in Fetuses with Congenital Cytomegalovirus Infection.

INTRODUCTION: The objective of this study was to investigate myocardial deformation of left (LV) and right ventricle (RV) using 2-dimensional speckle-tracking echocardiography (2D-STE) in fetuses with and without congenital cytomegalovirus (CMV) infection. METHODS: This was a prospective single-center study. Vertical transmission was defined by a positive CMV polymerase chain reaction (PCR) test on the amniotic fluid or on the neonate's urine. Fetuses were divided into group 1 and group 2 if CMV-PCR was positive or negative, respectively. LV and RV global longitudinal strain (GLS) values were obtained and adjusted for gestational age by calculating Z-scores. Univariate analysis was carried out to compare cardiac indices between group 1 and group 2. RESULTS: Fetuses from group 1 (n = 11) had a significantly lower LV myocardial shortening than those from group 2 (n = 32). GLS was -20.7 ± 5.2% and -26.3 ± 4.1%, respectively (p = 0.001). Similarly, GLS Z-score was lower (0.02 ± 0.72) in group 1 than in group 2 (-0.80 ± 0.59) (p = 0.001). Similarly, RV GLS Z-score was significantly impaired in group 1 compared to group 2 (-0.44 ± 1.03 vs. -1.04 ± 0.71, p = 0.041). CONCLUSION: Fetuses with congenital CMV showed subclinical biventricular myocardial dysfunction. Further studies are needed to confirm the potential role of 2D-STE in identifying fetuses with congenital CMV at risk of postnatal cardiovascular morbidities.

Electrocardiographic abnormalities in childhood cancer survivors treated with cardiotoxic therapy: a systematic review.

PURPOSE: The purpose of this study is to assess the available literature on the prevalence and risk factors of electrocardiographic (ECG) abnormalities after cardiotoxic treatment in childhood cancer survivors (CCS). METHODS: A literature search was performed within MEDLINE, EMBASE, and CENTRAL (1966-11/2020) and reference lists of relevant studies. Studies were eligible for inclusion if they reported ECG abnormalities ≥2 years after cancer diagnosis in ≥50 CCS treated with anthracyclines, RT involving the heart region and/or mitoxantrone. Information about population, treatment, outcome, and risk factors were extracted and risk of bias was assessed. RESULTS: Of 934 identified publications, 10 studies were included. Outcome definitions, treatment regimens, follow-up period, and risk of bias varied. These ECG abnormalities and prevalences were reported: major (5%-23%) and minor (12%) abnormalities according to the Minnesota Code, rhythm abnormalities (0%-12%), conduction abnormalities (0.3%-7.1%), depolarization abnormalities (0%), and repolarization abnormalities (0%-65%). The reported risk factors of ECG abnormalities (two studies) are male sex, anthracyclines, RT involving the heart region, and hypertension, although results were not univocal between studies and abnormalities. CONCLUSIONS: Multiple ECG abnormalities have been described in CCS ≥2 years from diagnosis, some of which can have important implications. Future research is needed to evaluate the exact long-term incidence and risk factors, and to investigate their clinical relevance and relation with cardiac dysfunction or future cardiac events. This could improve cardiac surveillance for CCS.

Cardiac abnormalities in girls with Turner syndrome: ECG abnormalities, myocardial strain imaging, and karyotype-phenotype associations.

Turner syndrome (TS) is a chromosomal condition which is associated with an increased prevalence of cardiac morbidity and mortality. In this cross-sectional study, Minnesota-based electrocardiographic (ECG) abnormalities, aortic dimensions, routine- and myocardial strain echocardiographic parameters, and karyotype-cardiac phenotype associations were assessed in girls with TS. In total, 101 girls with TS (0-18 years) were included. The prevalence of major ECG abnormalities was 2% (T-wave abnormalities) and 39% had minor ECG abnormalities. Dilatation of the ascending aorta (z-score > 2) was present in 16%, but the prevalence was much lower when using TS-specific z-scores. No left ventricular hypertrophy was detected and the age-matched global longitudinal strain was reduced in only 6% of the patients. Cardiac abnormalities seemed more common in patients with a non-mosaic 45,X karyotype compared with other karyotypes, although no statistically significant association was found. Lowering the frequency of echocardiography and ECG screening might be considered in girls with TS without cardiovascular malformations and/or risk factors for aortic dissection. Nevertheless, a large prospective study is needed to confirm our results. The appropriate z-score for the assessment of aortic dilatation remains an important knowledge gap. The karyotype was not significantly associated with the presence of cardiac abnormalities, therefore cardiac screening should not depend on karyotype alone.

Echocardiography protocol for early detection of cardiac dysfunction in childhood cancer survivors in the multicenter DCCSS LATER 2 CARD study: Design, feasibility, and reproducibility.

BACKGROUND: Cardiotoxicity is a well-known side effect after anthracyclines and chest radiotherapy in childhood cancer survivors (CCS). The DCCSS LATER 2 CARD (cardiology) study includes evaluation of echocardiographic measurements for early identification of CCS at highest risk of developing heart failure. This paper describes the design, feasibility, and reproducibility of the echocardiography protocol. METHODS: Echocardiograms from CCS and sibling controls were prospectively obtained at the participating centers and centrally analyzed. We describe the image acquisition, measurement protocol, and software-specific considerations for myocardial strain analyses. We report the feasibility of the primary outcomes of systolic and diastolic function, as well as reproducibility analyses in 30 subjects. RESULTS: We obtained 1,679 echocardiograms. Biplane ejection fraction (LVEF) measurement was feasible in 91% and 96% of CCS and siblings, respectively, global longitudinal strain (GLS) in 80% and 91%, global circumferential strain (GCS) in 86% and 89%, and ≥2 diastolic function parameters in 99% and 100%, right ventricle free wall strain (RVFWS) in 57% and 65%, and left atrial reservoir strain (LASr) in 72% and 79%. Intra-class correlation coefficients for inter-observer variability were 0.85 for LVEF, 0.76 for GLS, 0.70 for GCS, 0.89 for RVFWS and 0.89 for LASr. Intra-class correlation coefficients for intra-observer variability were 0.87 for LVEF, 0.82 for GLS, 0.82 for GCS, 0.85 for RVFWS and 0.79 for LASr. CONCLUSION: The DCCSS LATER 2 CARD study includes a protocolized echocardiogram, with feasible and reproducible primary outcome measurements. This ensures high-quality outcome data for prevalence estimates and for reliable comparison of cardiac function parameters.

Diagnostic tools for early detection of cardiac dysfunction in childhood cancer survivors: Methodological aspects of the Dutch late effects after childhood cancer (LATER) cardiology study.

BACKGROUND: Cancer therapy-related cardiac dysfunction and heart failure are major problems in long-term childhood cancer survivors (CCS). We hypothesize that assessment of more sensitive echo- and electrocardiographic measurements, and/or biomarkers will allow for improved recognition of patients with cardiac dysfunction before heart failure develops, and may also identify patients at lower risk for heart failure. OBJECTIVE: To describe the methodology of the Dutch LATER cardiology study (LATER CARD). METHODS: The LATER CARD study is a cross-sectional study in long-term CCS treated with (potentially) cardiotoxic cancer therapies and sibling controls. We will evaluate 1) the prevalence and associated (treatment related) risk factors of subclinical cardiac dysfunction in CCS compared to sibling controls and 2) the diagnostic value of echocardiography including myocardial strain and diastolic function parameters, blood biomarkers for cardiomyocyte apoptosis, oxidative stress, cardiac remodeling and inflammation and ECG or combinations of them in the surveillance for cancer therapy-related cardiac dysfunction. From 2017 to 2020 we expect to include 1900 CCS and 500 siblings. CONCLUSIONS: The LATER CARD study will provide knowledge on different surveillance modalities for detection of cardiac dysfunction in long-term CCS at risk for heart failure. The results of the study will enable us to improve long-term follow-up surveillance guidelines for CCS at risk for heart failure.

Diastolic strain time as predictor for systolic dysfunction among patients with active breast cancer.

BACKGROUND: Although diastolic dysfunction is common among patients treated with cancer therapy, no clear evidence has been shown that it predicts systolic dysfunction. This study evaluated the correlation of diastolic strain time (Dst) with the routine echocardiography diastolic parameters and estimated its role in the early detection of cardiotoxicity among patients with active breast cancer. METHODS: Data were collected as part of the Israel Cardio-Oncology Registry (ICOR), a prospective registry enrolling all adult patients referred to the cardio-oncology clinic. All patients with breast cancer, planned for Doxorubicin therapy, were included. Echocardiography, including global longitudinal systolic strain (GLS) and Dst, was assessed at baseline before chemotherapy (T1), during Doxorubicin therapy (T2) and after the completion of Doxorubicin therapy (T3). Cardiotoxicity was determined by GLS relative reduction of ≥15%. Dst was assessed as the time measured (ms) of the myocardium lengthening during diastole. RESULTS: Among 69 patients, 67 (97.1%) were females with a mean age of 52 ± 13 years. Dst was significantly associated with the routine diastolic parameters. Significant GLS reduction was observed in 10 (20%) patients at T3. Both in a univariate and a multivariate analyses, the change in Ds basal time from T1 to T2 emerged to be significantly associated with GLS reduction at T3 (P < .04). CONCLUSIONS: Among breast cancer patients, Dst showed high correlation to the routine diastolic echocardiography parameters. Change in Ds basal time emerged associated with clinically significant systolic dysfunction as measured by GLS reduction.

Cardiac function in paediatric patients with congenital adrenal hyperplasia due to 21 hydroxylase deficiency.

BACKGROUND: Hyperandrogenism and exogenous glucocorticoid excess may cause unfavourable changes in the cardiovascular risk profile of patients with congenital adrenal hyperplasia (CAH). OBJECTIVE: To evaluate the cardiac function in paediatric patients with CAH. PATIENTS AND METHODS: Twenty-seven paediatric patients with CAH, aged 8-16 years, were evaluated by physical examination, electrocardiogram (ECG), conventional echocardiography, tissue Doppler imaging and two-dimensional (2D) myocardial strain (rate) imaging. Results were compared to 27 age- and gender- matched healthy controls. RESULTS: No signs of left ventricular hypertrophy or dilatation were detected on echocardiography. ECG revealed a high prevalence (25.9%) of incomplete right bundle branch block. Left ventricular posterior wall thickness in diastole (LVPWd) was significantly lower in patients with CAH compared to controls (5.55 vs 6.53 mm; P = .009). The LVPWd Z-score was significantly lower in patients with CAH yet within the normal range (-1.12 vs -0.35; P = .002). Isovolumetric relaxation time was significantly lower in patients with CAH (49 vs 62 ms; P = .003). Global longitudinal, radial and circumferential strain was not significantly different compared to controls. Global radial strain rate was significantly higher compared to healthy controls (2.58 vs 2.06 1/s; P = .046). Global longitudinal strain was negatively correlated with 24-hour blood pressure parameters. CONCLUSION: Cardiac evaluation of paediatric patients with CAH showed no signs of left ventricular hypertrophy or ventricular dilatation. LVPWd was lower in patients with CAH than in controls but within the normal range. A shorter isovolumetric relaxation time in patients with CAH may be a sign of mild left ventricular diastolic dysfunction.

Is screening for abnormal ECG patterns justified in long-term follow-up of childhood cancer survivors treated with anthracyclines?

BACKGROUND: ECG and echocardiography are noninvasive screening tools to detect subclinical cardiotoxicity in childhood cancer survivors (CCSs). Our aims were as follows: (1) assess the prevalence of abnormal ECG patterns, (2) determine the agreement between abnormal ECG patterns and echocardiographic abnormalities; and (3) determine whether ECG screening for subclinical cardiotoxicity in CCSs is justified. PROCEDURE: We retrospectively studied ECG and echocardiography in asymptomatic CCSs more than 5 years after anthracycline treatment. Exclusion criteria were abnormal ECG and/or echocardiogram at the start of therapy, incomplete follow-up data, clinical heart failure, cardiac medication, and congenital heart disease. ECG abnormalities were classified using the Minnesota Code. Level of agreement between ECG and echocardiography was calculated with Cohen kappa. RESULTS: We included 340 survivors with a mean follow-up of 14.5 years (range 5-32). ECG was abnormal in 73 survivors (21.5%), with ventricular conduction disorders, sinus bradycardia, and high-amplitude R waves being most common. Prolonged QTc (>0.45 msec) was found in two survivors, both with a cumulative anthracycline dose of 300 mg/m2 or higher. Echocardiography showed abnormalities in 44 survivors (12.9%), mostly mild valvular abnormalities. The level of agreement between ECG and echocardiography was low (kappa 0.09). Male survivors more often had an abnormal ECG (corrected odds ratio: 3.00, 95% confidence interval: 1.68-5.37). CONCLUSIONS: Abnormal ECG patterns were present in 21% of asymptomatic long-term CCSs. Lack of agreement between abnormal ECG patterns and echocardiographic abnormalities may suggest that ECG is valuable in long-term follow-up of CCSs. However, it is not clear whether these abnormal ECG patterns will be clinically relevant.

AGORA, a data- and biobank for birth defects and childhood cancer.

BACKGROUND: Research regarding the etiology of birth defects and childhood cancer is essential to develop preventive measures, but often requires large study populations. Therefore, we established the AGORA data- and biobank in the Netherlands. In this study, we describe its rationale, design, and ongoing data collection. METHODS: Children diagnosed with and/or treated for a structural birth defect or childhood cancer and their parents are invited to participate in the AGORA data- and biobank. Controls are recruited through random sampling from municipal registries. The parents receive questionnaires about demographics, family and pregnancy history, health status, prescribed medication, lifestyle, and occupational exposures before and during the index pregnancy. In addition, blood or saliva is collected from children and parents, while medical records are reviewed for diagnostic information. RESULTS: So far, we have collected data from over 6,860 families (3,747 birth defects, 905 childhood cancers, and 2,208 controls). The types of birth defects vary widely and comprise malformations of the digestive, respiratory, and urogenital tracts as well as facial, cardiovascular, kidney, skeletal, and central nervous system anomalies. The most frequently occurring childhood cancer types are acute lymphatic leukemia, Hodgkin and non-Hodgkin lymphoma, Wilms' tumor, and brain and spinal cord tumors. Our genetic and/or epidemiologic studies have been focused on hypospadias, anorectal malformations, congenital anomalies of the kidney and urinary tract (CAKUT), and orofacial clefts. CONCLUSION: The large AGORA data- and biobank offers great opportunities for investigating genetic and nongenetic risk factors for disorders in children and is open to collaborative initiatives. Birth Defects Research (Part A) 106:675-684, 2016. © 2016 Wiley Periodicals, Inc.

Long-Term Serial Follow-Up of Pulmonary Artery Size and Wall Shear Stress in Fontan Patients.

Pulmonary arterial (PA) flow is abnormal after the Fontan operation and is marked by a lack of pulsatility. We assessed the effects of this abnormal flow on the size and function of the PA's in Fontan patients in long-term serial follow-up. Twenty-three Fontan patients with serial follow-up were included. Median age was 11.1 (9.5-16.0) years at baseline and 15.5 (12.5-22.7) years at follow-up. Median follow-up duration was 4.4 (4.0-5.8) years. Flow and size of the left pulmonary artery were determined using phase-contrast MRI. From this wall shear stress (WSS), distensibility and pulsatility were determined. A group of healthy peers was included for reference. Flow and pulsatility were significantly lower in patients than in controls (p < 0.001). Mean area was comparable in patients and controls, but distensibility was significantly higher in controls (p < 0.001). Mean and peak WSS were significantly lower in Fontan patients (p < 0.001). Between baseline and follow-up, there was a significant increase in normalized flow (15.1 (14.3-19.1) to 18.7 (14.0-22.6) ml/s/m(2), p = 0.023). Area, pulsatility, distensibility and WSS did not change, but there was a trend toward a lower mean WSS (p = 0.068). Multivariable regression analysis showed that flow, area and age were important predictors for WSS. WSS in Fontan patients is decreased compared to healthy controls and tends to decrease further with age. Pulsatility and distensibility are significantly lower compared to healthy controls. Pulmonary artery size, however, is not significantly different from healthy controls and long-term growth after Fontan operation is proportionate to body size.

Does functional health status predict health-related quality of life in children after Fontan operation?

PURPOSE: It is important to identify those children with a Fontan circulation who are at risk for impaired health-related quality of life. We aimed to determine the predictive value of functional health status - medical history and present medical status - on both physical and psychosocial domains of health-related quality of life, as reported by patients themselves and their parents. METHODS: We carried out a prospective cross-sectional multi-centre study in Fontan patients aged between 8 and 15, who had undergone staged completion of total cavopulmonary connection according to a current technique before the age of 7 years. Functional health status was assessed as medical history - that is, age at Fontan, type of Fontan, ventricular dominance, and number of cardiac surgical procedures - and present medical status - assessed with magnetic resonance imaging, exercise testing, and rhythm assessment. Health-related quality of life was assessed with The TNO/AZL Child Questionnaire Child Form and Parent Form. RESULTS: In multivariate prediction models, several medical history variables, such as more operations post-Fontan completion, lower age at Fontan completion, and dominant right ventricle, and present medical status variables, such as smaller end-diastolic volume, a higher score for ventilatory efficiency, and the presence of sinus node dysfunction, predicted worse outcomes on several parent-reported and self-reported physical as well as psychosocial health-related quality of life domains. CONCLUSIONS: Medical history and worse present medical status not only predicted worse physical parent-reported and self-reported health-related quality of life but also worse psychosocial health-related quality of life and subjective cognitive functioning. These findings will help in identifying patients who are at risk for developing impaired health-related quality of life.

Mending Hearts and Building Bridges: The Save a Child's Heart Foundation.

CONTEXT: Save a Child's Heart addresses the challenges of heart care for children in underdeveloped countries. OBJECTIVE: Save a Child's Heart has created a center of excellence for pediatric cardiac care at the Wolfson Medical Center in Israel, helped develop partner sites for evaluation and referral, and trained medical teams to return and build their own capacity for local cardiac care. RESULTS: Save a Child's Heart has treated more than 3600 children from 48 countries, with 50% from Iraq, Jordan, the Palestinian Authority, and Syria. In cooperation with the Palestinian Authority, Save a Child's Heart has examined more than 6000 children and treated 1750 children, trained 21 medical personnel, and conducted seminars for Palestinian medical personnel. The "Heart of the Matter Project," funded by the European Union, US Agency for International Development, the Palestinian Ministry of Health, and the Israeli Ministry of Regional Cooperation, is currently training a team at the Wolfson Medical Center from the Palestine Medical Complex in Ramallah and provides funds for Palestinian children's care in Israel. CONCLUSIONS: Save a Child's Heart is a model of a global humanitarian health care initiative with a single focus on heart disease in children. The "Heart of the Matter Project" is a model of health care based on regional cooperation despite local political tensions.

Early myocardial deformation abnormalities in breast cancer survivors.

To evaluate the role of 2D myocardial strain (rate) imaging in the detection of early subclinical cardiotoxicity in breast cancer survivors treated with an anthracycline-based chemotherapeutic regimen. 57 adult breast cancer survivors were analyzed 1 year after therapy. All patients underwent biomarker analysis and 2D echocardiography consisting of conventional echocardiographic and strain (rate) parameters. Conventional echocardiographic values were normal. Global longitudinal strain was normal, but 18 % of patients showed a >2 SD decrease when individually compared to reference values. This subgroup showed a decrease in end-systolic and end-diastolic volumes and an increase in left ventricular mass. Radial and circumferential strain rates were significantly decreased in the whole study group. 2D myocardial strain (rate) imaging showed abnormalities in breast cancer survivors, while conventional echocardiographic values remained normal, rendering 2D myocardial strain (rate) imaging an interesting tool for the early detection of anthracycline-induced cardiotoxicity.

CHD7 mutations are not a major cause of atrioventricular septal and conotruncal heart defects.

Since 2004, CHD7 mutations have been a known cause of CHARGE (Coloboma, Heart defects, Atresia of choane, Retardation of growth and development, Genital hypoplasia, Ear anomalies) syndrome, but the full clinical spectrum of CHD7 mutations is only now gradually emerging. CHD7 mutations have been identified in patients who do not fulfill the clinical criteria for CHARGE syndrome and in patients with overlapping syndromes. Variable congenital heart defects occur in the majority of patients with CHD7 mutations, with an overrepresentation of atrioventricular septal defects and conotruncal heart defects. This prompted us to study CHD7 in 46 patients with these heart defects and one other feature of CHARGE syndrome. We identified two CHD7 variants that were inherited from a healthy parent (c.3778 + 17C > T, c.7294G > A), but no pathogenic CHD7 mutations. We conclude that CHD7 mutations are not a major cause of the atrioventricular septal defects and conotruncal heart defects, not even if one extra phenotypic feature of CHARGE syndrome is present. Therefore, CHD7 analysis should not be performed routinely in this group of patients. However, we do recommend adding CHD7 to massive parallel sequencing gene panels for diagnostic work in patients with syndromic heart defects.

Autosomal recessive dilated cardiomyopathy due to DOLK mutations results from abnormal dystroglycan O-mannosylation.

Genetic causes for autosomal recessive forms of dilated cardiomyopathy (DCM) are only rarely identified, although they are thought to contribute considerably to sudden cardiac death and heart failure, especially in young children. Here, we describe 11 young patients (5-13 years) with a predominant presentation of dilated cardiomyopathy (DCM). Metabolic investigations showed deficient protein N-glycosylation, leading to a diagnosis of Congenital Disorders of Glycosylation (CDG). Homozygosity mapping in the consanguineous families showed a locus with two known genes in the N-glycosylation pathway. In all individuals, pathogenic mutations were identified in DOLK, encoding the dolichol kinase responsible for formation of dolichol-phosphate. Enzyme analysis in patients' fibroblasts confirmed a dolichol kinase deficiency in all families. In comparison with the generally multisystem presentation in CDG, the nonsyndromic DCM in several individuals was remarkable. Investigation of other dolichol-phosphate dependent glycosylation pathways in biopsied heart tissue indicated reduced O-mannosylation of alpha-dystroglycan with concomitant functional loss of its laminin-binding capacity, which has been linked to DCM. We thus identified a combined deficiency of protein N-glycosylation and alpha-dystroglycan O-mannosylation in patients with nonsyndromic DCM due to autosomal recessive DOLK mutations.

Dealing with Ebstein's anomaly.

Ebstein's anomaly is a complex congenital disorder of the tricuspid valve. Presentation in neonatal life and (early) childhood is common. Disease severity and clinical features vary widely and require a patient-tailored treatment. In this review, we describe the natural history of children and adolescents with Ebstein's anomaly, including symptoms and signs presenting at diagnosis. Current classification strategies of Ebstein's anomaly are discussed. We report on diagnostic methods for establishing the severity of disease that might enhance decision on the timing of surgical intervention. Furthermore, we describe different surgical options for severely ill neonates and multiple surgical interventions after infancy. Only with ample knowledge and understanding of the above, this complex and diverse group of patients can be correctly treated in order to improve not only duration, but also quality of life.

Cardiovascular health in pediatric patients with X-linked hypophosphatemia under two years of burosumab therapy.

Introduction: X-linked hypophosphatemia (XLH) is caused by an inactivating mutation in the phosphate-regulating endopeptidase X-linked (PHEX) gene whose defective product fails to control phosphatonin fibroblast growth factor 23 (FGF23) serum levels. Although elevated FGF23 levels have been linked with detrimental cardiac effects, the cardiologic outcomes in XLH patients have been subject to debate. Our study aimed to evaluate the prevalence and severity of cardiovascular morbidity in pediatric XLH patients before, during, and after a 2-year treatment period with burosumab, a recombinant anti-FGF23 antibody. Methods: This prospective observational study was conducted in a tertiary medical center, and included 13 individuals with XLH (age range 0.6-16.2 years) who received burosumab every 2 weeks. Clinical assessment at treatment initiation and after .5, 1, and 2 years of uninterrupted treatment included anthropometric measurements and cardiologic evaluations (blood pressure [BP], electrocardiogram, conventional echocardiography, and myocardial strain imaging). Results: The linear growth of all patients improved significantly (mean height z-score: from -1.70 ± 0.80 to -0.96 ± 1.08, P=0.03). Other favorable effects were decline in overweight/obesity rates (from 46.2% to 23.1%) and decreased rates of elevated BP (systolic BP from 38.5% to 15.4%; diastolic BP from 38.5% to 23.1%). Electrocardiograms revealed no significant abnormality throughout the study period. Cardiac dimensions and myocardial strain parameters were within the normative range for age at baseline and remained unchanged during the study period. Conclusion: Cardiologic evaluations provided reassurance that 2 years of burosumab therapy did not cause cardiac morbidity. The beneficial effect of this treatment was a reduction in cardiovascular risk factors, as evidenced by the lower prevalence of both overweight/obesity and elevated BP.

Cardiac screening in pediatric patients with neurofibromatosis type 1: similarities with Noonan syndrome?

Both Neurofibromatosis type 1 (NF1) and Noonan syndrome (NS) are RASopathies. Characteristic cardiac phenotypes of NS, including specific electrocardiographic changes, pulmonary valve stenosis and hypertrophic cardiomyopathy have not been completely studied in NF1. PURPOSE: The aims of this study were to assess: (1) similarities in the prevalence and types of ECG and conventional echocardiographic findings described in NS in asymptomatic patients with NF1, and (2) the presence of discrete myocardial dysfunction in NF1 patients using myocardial strain imaging. METHODS: Fifty-eight patients with NF1 (ages 0-18 years), and thirty-one age-matched healthy controls underwent cardiac assessment including blood pressure measurements, a 12-lead ECG, and detailed echocardiography. Quantification of cardiac chamber size, mass and function were measured using conventional echocardiography. Myocardial strain parameters were assessed using 2-Dimensional (2D) Speckle tracking echocardiography. RESULTS: Asymptomatic patients with NF1 had normal electrocardiograms, none with the typical ECG patterns described in NS. However, patients with NF1 showed significantly decreased calculated Z scores of the left ventricular internal diameter in diastole and systole, reduced left ventricular mass index and a higher incidence of cardiac abnormal findings, mainly of the mitral valve, in contrast to the frequently described types of cardiac abnormalities in NS. Peak and end systolic global circumferential strain were the only significantly reduced speckle tracking derived myocardial strain parameter. CONCLUSIONS: Children with NF1 demonstrated more dissimilarities than similarities in the prevalence and types of ECG and conventional echocardiographic findings described in NS. The role of the abnormal myocardial strain parameter needs to be explored.