Shankar Baskar

Tartrate-resistant acid phosphatase deficiency causes a bone dysplasia with autoimmunity and a type I interferon expression signature

We studied ten individuals from eight families showing features consistent with the immuno-osseous dysplasia spondyloenchondrodysplasia. Of particular note was the diverse spectrum of autoimmune phenotypes observed in these individuals (cases), including systemic lupus erythematosus, Sjögrens syndrome, hemolytic anemia, thrombocytopenia, hypothyroidism, inflammatory myositis, Raynauds disease and vitiligo. Haplotype data indicated the disease gene to be on chromosome 19p13, and linkage analysis yielded a combined multipoint log10 odds (LOD) score of 3.6. Sequencing of ACP5, encoding tartrate-resistant acid phosphatase, identified biallelic mutations in each of the cases studied, and in vivo testing confirmed a loss of expressed protein. All eight cases assayed showed elevated serum interferon alpha activity, and gene expression profiling in whole blood defined a type I interferon signature. Our findings reveal a previously unrecognized link between tartrate-resistant acid phosphatase activity and interferon metabolism and highlight the importance of type I interferon in the genesis of autoimmunity.

Adams–Oliver syndrome: Additions to the clinical features and possible role of BMP pathway†

We report on a patient with Adams–Oliver syndrome, a condition characterized by scalp and limb defects. In addition we noted in our patient a significant delay in the bone age and an abnormal distal phalanx in one of her fingers manifesting clinically as a broad finger tip. Both these features hitherto unreported add to the phenotypic spectrum of the condition. The underlying etiopathogenesis of this condition has remained in the domain of hypothesis, with none being conclusive. Based on the characteristic features of AOS and our report of delayed bone age, we postulate a role played by the bone morphogenetic protein pathway in the causation of this enigmatic condition. In the background of this postulation and the report of an unusual hand anomaly, a literature review on the various pathogenetic mechanisms and anomalies of the hand reported in AOS is presented.

The Use of IL-1 Receptor Antagonist (Anakinra) in Idiopathic Recurrent Pericarditis: A Narrative Review

Recurrent pericarditis is a complication of acute pericarditis in 20–30% of the patients and is usually idiopathic in nature. The underlying pathogenesis of this condition remains unclear, although immune-mediated mechanisms seem likely. A subgroup of these patients with refractory symptoms can be challenging to manage, and multiple immunosuppressive medications have been used without consistent benefit. Anakinra, an interleukin-1 receptor antagonist, has been used in treatment of rheumatoid arthritis and autoinflammatory syndromes. Preliminary evidence suggests that anakinra could be a promising therapy for idiopathic recurrent pericarditis. In this narrative review, we summarize the current understanding of the etiopathogenesis of idiopathic recurrent pericarditis, mechanism of action of anakinra, and the preliminary evidence, supporting the use of anakinra in pericarditis.

Compound Heterozygous Mutations in the SCN5A-Encoded Nav1.5 Cardiac Sodium Channel Resulting in Atrial Standstill and His-Purkinje System Disease

An 11-year-old girl on evaluation for syncope was found to have progressive sinus node dysfunction and His-Purkinje system disease with atrial standstill. Genetic analysis revealed compound heterozygous mutations of the SCN5A gene in a novel combination.

Cardiovascular risk factors and cardiac disorders in long‐term survivors of pediatric liver transplantation

The MetS and cardiovascular disease are leading causes of late morbidity in adult liver transplantation recipients; however, limited data are available in pediatric liver transplantation. A single‐center retrospective review was undertaken for patients who had a liver transplantation before 18 yr of age and were >5 yr post‐transplantation, to study the prevalence of MetS, its components, and cardiac disorders. Fifty‐eight patients were included in the study with a mean age at transplantation of 6.3 ± 6.1 yr and mean follow‐up of 14.1 ± 6.0 yr. Of the study group, 41.4% were overweight or obese, with ongoing prednisone use and increased duration of follow‐up being significant risk factors. Fifty‐three patients had sufficient data for determining MetS, which was present in 17% of the patients. Although the prevalence of MetS is low in pediatric liver transplant recipients, it is associated with CKD and prednisone therapy (p < 0.05). Echocardiography data were available for 23 patients, of whom 43.4% had LVH and 13% had evidence of PH. The spectrum of cardiac disorders in this population is much wider than in adults.

Fetal intracranial calcification: Pseudo-TORCH phenotype and discussion of related phenotypes†

Fetal intracranial calcification (ICC) noted during antenatal imaging poses a diagnostic challenge. Although this presentation is most commonly associated with intrauterine infection, non‐infectious causes of fetal ICC have been reported and include metabolic, genetic, or hemodynamic conditions. We report on a patient with antenatally detected extensive ICC, in whom postnatal imaging revealed a distinctive band‐like ICC with abnormal gyral pattern and a negative serology for TORCH infections. Such a constellation of findings have been previously described under the terminology of “pseudo‐TORCH phenotype,” and we posit that our patient represents this entity. Our patient had unreported dysmorphic features, which expands the phenotypic spectrum of this recently described heterogenous condition. In addition we report on the progression of the phenotype both clinically and radiologically. In view of the limited information available for the differential diagnosis of fetal ICC, we also review the available literature on this topic.

Genotype-phenotype correlation in long QT syndrome

Congenital long QT syndrome, caused by a cardiac channelopathy, is a leading cause of sudden cardiac death in the young population. In total, 16 genes have been implicated in this condition, with three genes being the most commonly affected. Long QT syndrome is one of the earliest conditions for which a genotype specific treatment was designed. This genotype-phenotype correlation extends to involve the clinical presentation, electrocardiographic manifestation and treatment strategies. It is necessary for the clinician treating these patients to be cognizant of the important role played by the genotype in order to best provide counseling and treatment options to this unique population.

Arrhythmia burden and related outcomes in Eisenmenger syndrome

BACKGROUND Patients with Eisenmenger syndrome have a shorter lifespan than the general population. A significant proportion develop arrhythmia and some, sudden death. OBJECTIVE The aims of this study were to characterize the frequency, type and effects of arrhythmias in adult patients with Eisenmengers syndrome and to identify risk factors for arrhythmias. METHODS This retrospective study included patients aged ≥ 18 years of age with Eisenmengers syndrome from three institutions. Arrhythmias were noted from electrocardiograms and Holter study reviews. RESULTS A total of 167 patients, 96 females, 63 males (gender not available in 9 patients) were included in this study. The mean age was 38 ± 9 years (range: 18-63 years) with a majority in NYHA functional class II or III (57% and 32% respectively). Twenty-eight patients (17%) had significant tachyarrhythmia: paroxysmal supraventricular tachycardia (8 patients, 29%), atrial fibrillation (6 patients, 21%), atrial fibrillation and flutter (2 patients, 7%), nonsustained ventricular tachycardia (6 patients, 21%) and sustained ventricular tachycardia (6 patients, 21%). Among the entire study group, 26 patients (16%) were currently on antiarrhythmic therapy and 77 patients (49%) were on advanced therapies for pulmonary hypertension. Down syndrome was present in 78 patients (46%). There were 21 (13%) documented deaths, of which 8 (5%) were sudden death. Patients with arrhythmia were older [P = .01] and were more likely to have atrioventricular valvar regurgitation [Odds ratio: 4.33]. Advanced pulmonary hypertension therapy was associated with decreased all-cause mortality in logistic regression analysis [odds ratio: 0.31], while antiarrhythmic therapy was associated with sudden death [odds ratio: 6.24]. CONCLUSIONS Arrhythmias are common among patients with Eisenmenger syndrome occurring in around 1 in 5 individuals and are associated with all-cause mortality and sudden death.

First‐Line Antiarrhythmic Transplacental Treatment for Fetal Tachyarrhythmia: A Systematic Review and Meta‐Analysis

Background There is no consensus on the most effective and best tolerated first‐line antiarrhythmic treatment for fetal tachyarrhythmia. The purpose of this systematic review and meta‐analysis was to compare the efficacy, safety, and fetal–maternal tolerance of first‐line monotherapies for fetal supraventricular tachycardia and atrial flutter. Methods and Results A comprehensive search of several databases was conducted through January 2017. Only studies that made a direct comparison between first‐line treatments of fetal tachyarrhythmia were included. Outcomes of interest were termination of fetal tachyarrhythmia, fetal demise, and maternal complications. Ten studies met inclusion criteria, with 537 patients. Overall, 291 patients were treated with digoxin, 137 with flecainide, 102 with sotalol, and 7 with amiodarone. Digoxin achieved a lower rate of supraventricular tachycardia termination compared with flecainide (odds ratio [OR]: 0.773; 95% confidence interval [CI], 0.605–0.987; I2=34%). In fetuses with hydrops fetalis, digoxin had lower rates of tachycardia termination compared with flecainide (OR: 0.412; 95% CI, 0.268–0.632; I2=0%). There was no significant difference in the incidence of maternal side effects between digoxin and flecainide groups (OR: 1.134; 95% CI, 0.129–9.935; I2=80.79%). The incidence of maternal side effects was higher in patients treated with digoxin compared with sotalol (OR: 3.148; 95% CI, 1.468–6.751; I2=0%). There was no difference in fetal demise between flecainide and digoxin (OR: 0.767; 95% CI, 0.140–4.197; I2=44%). Conclusions Flecainide may be more effective treatment than digoxin as a first‐line treatment for fetal supraventricular tachycardia.

Cardiovascular risk in pediatric nonalcoholic fatty liver disease: recent advances

Abstract Nonalcoholic fatty liver disease (NAFLD) is the most common form of pediatric chronic liver disease in developed countries. NAFLD has risen to epidemic proportions paralleling that of childhood obesity. It is becoming increasingly evident that NAFLD is strongly linked with cardiovascular disease (CVD), which is the leading cause of mortality in the adult NAFLD population. It is very important for physicians caring for children being cognizant of the potential role of childhood NAFLD as an independent risk factor for CVD. Childhood is a time period where subclinical CVD can be detected, giving us the potential ability to halt or reverse the disease process. In this review, we discuss recent evidence linking childhood NAFLD to CVD and potential pathogenic links.