Heterogeneous Pulmonary Phenotypes in Filamin A Mutation-Related Lung Disease.

Background: Interstitial lung disease (ILD) has been recently reported in a few patients with pathogenic variants in the Filamin A (FLNA) gene with variable presentation and prognosis. This study evaluated the respiratory manifestations and clinical features in children with FLNA disease. Methods: We conducted a retrospective review of pediatric patients with variants in FLNA in a tertiary children's hospital. The clinical features, genotype, management, and outcomes were analyzed. Results: We identified 9 patients with variants in FLNA aged 15 months to 24 years, 4 females and 5 males. Six patients had abnormal chest imaging ranging from mild interstitial prominence to atelectasis, interstitial densities, and hyperinflation. Three patients with ILD presented during the neonatal period or early infancy with respiratory distress or respiratory failure requiring supplemental oxygen or assisted ventilation via tracheostomy. We report male twins with the same FLNA variant and lung disease, but different ages and clinical features at presentation eventually culminating in respiratory failure requiring assisted ventilation. All patients had FLNA variants identified by FLNA sequencing, had abnormal echocardiograms, and none of the patients underwent lung biopsy or lung transplantation. The outcomes were variable and could be as severe as chronic respiratory failure. Conclusion: The wide spectrum of respiratory manifestations and abnormal chest imaging in our study highlights the importance of evaluation for lung disease in patients with variants in FLNA. FLNA sequencing in suspected cases with ILD may obviate the need for a lung biopsy, prompt surveillance for progressive lung disease, and evaluation for associated clinical features.

Treatment of attention deficit/hyperactivity disorder in children with CHD.

INTRODUCTION: The prevalence of attention deficit/hyperactivity disorder in the general population is common and is now diagnosed in 4%-12% of children. Children with CHD have been shown to be at increased risk for attention deficit/hyperactivity disorder. Case reports have led to concern regarding the use of attention deficit/hyperactivity disorder medications in children with underlying CHD. We hypothesised that medical therapy for patients with CHD and attention deficit/hyperactivity disorder is safe. METHODS: A single-centre, retrospective chart review was performed evaluating for adverse events in patients aged 4-21 years with CHD who received attention deficit/hyperactivity disorder therapy over a 5-year span. Inclusion criteria were a diagnosis of CHD and concomitant medical therapy with amphetamines, methylphenidate, or atomoxetine. Patients with trivial or spontaneously resolved CHD were excluded from analysis. RESULTS: In 831 patients with CHD who received stimulants with a mean age of 12.9 years, there was only one adverse cardiovascular event identified. Using sensitivity analysis, our median follow-up time was 686 days and a prevalence rate of 0.21% of adverse events. This episode consisted of increased frequency of supraventricular tachycardia in a patient who had this condition prior to initiation of medical therapy; the condition improved with discontinuation of attention deficit/hyperactivity disorder therapy. CONCLUSION: The incidence of significant adverse cardiovascular events in our population was similar to the prevalence of supraventricular tachycardia in the general population. Our single-centre experience demonstrated no increased risk in adverse events related to medical therapy for children with attention deficit/hyperactivity disorder and underlying CHD. Further population-based studies are indicated to validate these findings.

Systolic ejection click versus split first heart sound: Are our ears deceiving us?

OBJECTIVE: Bicuspid aortic valve (BAV) disease is associated with potential lifetime complications, but auscultation of a BAV click is commonly missed or mistaken for a benign split first heart sound. Our objective was to determine whether pediatric cardiologists could reliably distinguish between BAV clicks and benign split first heart sounds. DESIGN: Quality evaluation project using de-identified recordings from an outpatient pediatric cardiology clinic. OUTCOME MEASURES: Twenty-one cardiologists listened to five de-identified recordings of pediatric heart sounds (three with BAV clicks, two with mitral components of benign split first heart sounds) and indicated whether they believed each recording was a BAV or split first heart sound. The accuracy of diagnoses was determined using percent agreement and calculated kappa coefficients for the cohort and subgroups based on those with less than 10 years of experience versus those with ≥10 years. To assess precision, a kappa extension was used for multiple raters to assess interrater agreement. RESULTS: Among participants, diagnostic accuracy of BAV click was 38%, while accuracy of split first heart sound was 41%. No participant correctly diagnosed all sounds. No difference in agreement was observed when stratifying by experience. Kappa was -0.11 (CI 95% -0.31 to 0.08) for all raters, -0.03 (CI 95% -0.39 to 0.33) for those with less than 10 years' experience, and -0.15 (CI 95% -0.38 to 0.08) for those with ≥10 years' experience. The kappa statistic among the 21 raters was 0.01 (95% CI -0.03 to 0.04), indicating poor precision among the raters. CONCLUSIONS: In this sample of pediatric cardiologists, the diagnostic accuracy of BAV clicks versus split first heart sounds was worse than chance. There was no association between years of experience and diagnostic accuracy. While further study is needed, these data suggest that an echocardiogram may be valuable when either a systolic ejection click or split first heart sound is heard.

Sickle Cell Disease with Cyanotic Congenital Heart Disease: Long-Term Outcomes in 5 Children.

Sickle cell disease is a risk factor for cerebrovascular accidents in the pediatric population. This risk is compounded by hypoxemia. Cyanotic congenital heart disease can expose patients to prolonged hypoxemia. To our knowledge, the long-term outcome of patients who have combined sickle cell and cyanotic congenital heart disease has not been reported. We retrospectively reviewed patient records at our institution and identified 5 patients (3 girls and 2 boys) who had both conditions. Their outcomes were uniformly poor: 4 died (age range, 12 mo-17 yr); 3 had documented cerebrovascular accidents; and 3 developed ventricular dysfunction. The surviving patient had developmental delays. On the basis of this series, we suggest mitigating hypoxemia, and thus the risk of stroke, in patients who have sickle cell disease and cyanotic congenital heart disease. Potential therapies include chronic blood transfusions, hydroxyurea, earlier surgical correction to reduce the duration of hypoxemia, and heart or bone marrow transplantation.

Exome sequencing of patients with histiocytoid cardiomyopathy reveals a de novo NDUFB11 mutation that plays a role in the pathogenesis of histiocytoid cardiomyopathy.

Histiocytoid cardiomyopathy (Histiocytoid CM) is a rare form of cardiomyopathy observed predominantly in newborn females that is fatal unless treated early in life. We have performed whole exome sequencing on five parent-proband trios and identified nuclear-encoded mitochondrial protein mutations in three cases. The molecular genetic basis of Histiocytoid CM remains unknown despite several hypotheses in medical literature. The findings presented in this manuscript may represent components of genetic etiologies for this heterogeneous disease. Two probands had de novo non-sense mutations in the second exon of the X-linked nuclear gene NDUFB11. A third proband was doubly heterozygous for inherited rare variants in additional components of complex I, NDUFAF2 and NDUFB9, confirming that Histiocytoid CM is genetically heterogeneous. In a fourth case, the proband with Histiocytoid CM inherited a mitochondrial mutation from her heteroplasmic mother, as did her brother who presented with cardiac arrhythmia. Strong candidate recessive or compound heterozygous variants were not found for this individual or for the fifth case. Although NDUFB11 has not been implicated before in cardiac pathology, morpholino-mediated knockdown of ndufb11 in zebrafish embryos generated defective cardiac tissue with cardiomegaly, looping defects, and arrhythmia which suggests the role of NDUFB11 in the pathogenesis of this abnormal cardiac pathology. Taken together, the unbiased whole exome sequencing approach confirms the suspected genetic heterogeneity of Histiocytoid CM. Therefore, the novel NDUFB11 mutation may cause a complex 1 deficiency in synergy with additional unknown mtDNA variants.

Lower extremity edema in a child due to pectus excavatum.

A previously healthy 11-year-old girl was referred for pediatric cardiology evaluation because of the development of progressive bilateral lower extremity swelling over the course of 2 years. Her prior workup had included a negative result for proteinuria and a negative ultrasound for deep venous thrombosis. On physical examination, in addition to her edema, she was found to have a severe pectus excavatum deformity, which prompted cardiac magnetic resonance imaging. This study demonstrated compression of the inferior vena cava. She underwent uneventful pectus repair with use of a modified Ravitch procedure and experienced complete resolution of her lower extremity edema.

Necrotizing enterocolitis in infants with congenital heart disease: the role of red blood cell transfusions.

Necrotizing enterocolitis (NEC) is a rare but catastrophic complication that may occur in newborns with congenital heart disease (CHD). In the preterm population, transfusion of red blood cells (RBCs) and use of RBCs with longer storage time have been independently associated with the development of NEC. To date, it is not known whether similar associations exist for the term newborn with CHD. This retrospective study identified the incidence of NEC among 1,551 newborns admitted to the authors' cardiac intensive care unit between 7 January 2002 and 7 January 2010. The study was limited to term newborns (>36 weeks gestation). To understand the impact of RBC transfusions on the development of NEC, a nested 2:1 matched case-control analysis was undertaken to compare RBC transfusion patterns between an age-matched group and a cardiac lesion-matched control group. In the study population, NEC developed in 45 term infants during the postoperative period. Of these 45 infants, 30 (66.7%) had single-ventricle heart defects, whereas 22 (48.8%) required surgery for aortic arch obstruction. The median patient age at NEC diagnosis was 21 days. The RBC transfusion rate was higher among the patients who experienced NEC (0.21/day) than among the control subjects (0.10/day) (p = 0.048). A multivariate analysis indicated that onset of NEC was associated with a greater number of RBC transfusions (odds ratio [OR] 1.83; 95% confidence interval [CI] 1.07-7.47; p = 0.045). The duration of RBC storage was not significantly longer in the NEC group (9 days) than in the control cohort (7 days) (p = 0.16). Increased exposure to RBC transfusions is associated with the development of NEC in term infants with CHD. Longer storage of RBCs does not appear to increase this risk. Although causality cannot be confirmed, these data prompt a careful review of RBC transfusion practices with this population.

The relationship between in-house attending coverage and nighttime extubation following congenital heart surgery*.

OBJECTIVES: Many cardiac ICUs have instituted 24/7 attending physician in-house coverage, which theoretically may allow for more expeditious weaning from ventilation and extubation. We aimed to determine whether this staffing strategy impacts rates of nighttime extubation and duration of mechanical ventilation. DESIGN: National data were obtained from the Virtual PICU System database for all patients admitted to the cardiac ICU following congenital heart surgery in 2011 who required postoperative mechanical ventilation. Contemporaneous data from our local institution were collected in addition to the Virtual PICU System data. The combined dataset (n = 2,429) was divided based on the type of nighttime staffing model in order to compare rates of nighttime extubation and duration of mechanical ventilation between units that used an in-house attending staffing strategy and those that employed nighttime residents, fellows, or midlevel providers only. MEASUREMENTS AND MAIN RESULTS: Institutions that currently use 24/7 in-house attending coverage did not demonstrate statistically significant differences in rates of nighttime extubation or the duration of mechanical ventilation in comparison to units without in-house attendings. Younger patients cared for in non-in-house attending units were more likely to require reintubation. CONCLUSIONS: Pediatric patients who have undergone congenital heart surgery can be safely and effectively extubated without the routine presence of an attending physician. The utilization of nighttime in-house attending coverage does not appear to have significant benefits on the rate of nighttime extubation and may not reduce the duration of mechanical ventilation in units that already use in-house residents, fellows, or other midlevel providers.

Hemolytic anemia after placement of an intraluminal pulmonary artery band.

A newborn with double outlet right ventricle, malposed great vessels, hypoplastic aortic arch, and coarctation of the aorta with no restriction to pulmonary blood flow underwent palliation with arch augmentation and placement of an intraluminal Dacron patch pulmonary artery band (PAB). She subsequently presented in shock because of profound hemolytic anemia. Her intraluminal PAB was taken down and replaced with a traditional extraluminal band with resolution of her hemolysis. It is possible that the use of Dacron for construction of the intraluminal PAB may have contributed significantly to this patient's hemolytic anemia.

Necrotising enterocolitis in infants with congenital heart disease: the role of enteral feeds.

OBJECTIVE: Necrotising enterocolitis is a rare, though catastrophic complication that may occur in term newborns with congenital heart disease. There is considerable controversy regarding the factors that lead to necrotising enterocolitis in this population. We sought to determine the incidence of necrotising enterocolitis among term and near-term newborns with congenital heart disease, focusing on the relationship of enteral feeding to this complication. METHODS: In this retrospective study, we identified the incidence of necrotising enterocolitis among 1551 newborns admitted to our cardiac intensive care unit between July 1, 2002 and July 1, 2010. In order to understand the impact of enteral feeding upon the development of necrotising enterocolitis, we undertook a nested 2:1 matched case-control analysis to compare feeding patterns in an age- and lesion-matched control population. RESULTS: Necrotising enterocolitis developed in 45 term or near-term infants (3%). The majority of these cases, 27 (60%), occurred in the post-operative period after the introduction of enteral feeds. This subgroup was used for matched analysis. There were no differences in enteral feeding patterns among the patients who developed necrotising enterocolitis and their matched controls. The overall mortality rate for patients who developed necrotising enterocolitis was 24.4% (11 out of 45). CONCLUSIONS: Despite numerous advances in the care of infants with congenital heart disease, necrotising enterocolitis remains a significant source of morbidity and mortality. In these infants, there is no clear relationship between enteral feeding patterns and the development of necrotising enterocolitis in the post-operative period. The benefits of graduated feeding advancements to avoid the development of necrotising enterocolitis remain unproven.

Coarctation of the aorta in the setting of tetralogy of Fallot: an uncommon cause of myocardial dysfunction.

The combination of both right and left heart obstruction has only rarely been described in the medical literature. We present three cases of coarctation of the aorta in patients with variants of tetralogy of Fallot and hypothesise that this condition may be more common than previously suspected and could represent a hidden cause of morbidity in patients with pulmonary atresia/ventricular septal defect.