Intracranial calcifications simulating Aicardi-Goutières syndrome in PARS2-related mitochondrial disease.

PARS2 encodes an aminoacyl-tRNA synthetase that catalyzes the ligation of proline to mitochondrial prolyl-tRNA molecules. Diseases associated with PARS2 primarily affect the central nervous system, causing early infantile developmental epileptic encephalopathies (EIDEE; DEE75; MIM #618437) with infantile-onset neurodegeneration. Dilated cardiomyopathy has also been reported in the affected individuals. About 10 individuals to date have been described with pathogenic biallelic variants in PARS2. While many of the reported individuals succumbed to the disease in the first two decades of life, autopsy findings have not yet been reported. Here, we describe neuropathological findings in a deceased male with evidence of intracranial calcifications in the basal ganglia, thalamus, cerebellum, and white matter, similar to Aicardi-Goutières syndrome. This report describes detailed autopsy findings in a child with PARS2-related mitochondrial disease and provides plausible evidence that intracranial calcifications may be a previously unrecognized feature of this disorder.

Arrhythmogenic cardiomyopathy is under-recognized in end-stage pediatric heart failure: A 36-year single-center experience.

BACKGROUND: Although ventricular failure is a late finding in adults with AC, we hypothesize that this is a presenting symptom in pediatric heart failure patients who undergo HT and that their ventricular arrhythmia burden could differentiate AC from other cardiomyopathies. METHODS: We performed a single-center retrospective cohort study reviewing 457 consecutive pediatric (≤18 years) HT recipients at our institution. Explanted hearts were examined to establish the primary diagnosis, based on pathologic findings. Demographic and clinical variables were compared between AC versus non-HCM cardiomyopathy cases. RESULTS: Forty-five percent (n = 205/457) had non-HCM cardiomyopathies as the underlying primary diagnosis. Ten cases (10/205 = 4.9%) were diagnosed with AC. All 10 had biventricular disease. In 8/10 patients (80%), AC diagnosis was unrecognized pre-HT. Compared with non-AC cardiomyopathies, the AC group was older at diagnosis (9.3 years vs. 4.3 years, p = .012) and transplant (11.1 years vs. 6.5 years, p = .010), had more ventricular arrhythmias (80.0% vs 32.8%, p = .003), and required more anti-arrhythmic use (80.0% vs 32.3%, p = .001). Genetic testing yielded causative pathogenic variants in all tested individuals (n = 5/5, 100%). CONCLUSION: AC is often an unrecognized cardiomyopathy pretransplant in children who undergo HT. Pediatric non-HCM phenotypes with heart failure who have a significant ventricular arrhythmia burden should be investigated for AC.

LMOD2-related dilated cardiomyopathy presenting in late infancy.

Leiomodin-2 (LMOD2) is an important regulator of the thin filament length, known to promote elongation of actin through polymerization at pointed ends. Mice with Lmod2 deficiency die around 3 weeks of age due to severe dilated cardiomyopathy (DCM), resulting from decreased heart contractility due to shorter thin filaments. To date, there have been three infants from two families reported with biallelic variants in LMOD2, presenting with perinatal onset DCM. Here, we describe a third family with a child harboring a previously described homozygous frameshift variant, c.1243_1244delCT (p.L415Vfs*108) with DCM, presenting later in infancy at 9 months of age. Family history was relevant for a sibling who died suddenly at 1 year of age after being diagnosed with cardiomegaly. LMOD2-related cardiomyopathy is a rare form of inherited cardiomyopathy resulting from thin filament length dysregulation and should be considered in genetic evaluation of newborns and infants with suspected autosomal recessive inheritance or sporadic early onset cardiomyopathy.

Extrahepatic Nonreticuloendothelial Siderosis Is Not Specific to Gestational Alloimmune Liver Disease.

Autopsy reports of 78 stillbirths and early infant deaths (up to age 8 weeks) were reviewed to investigate the prevalence of extrahepatic nonreticuloendothelial siderosis (EHNRS) in the context of neonatal liver failure. Of these, 10 liveborns (12.8%), M:F 3:2, with mean gestational age 37.6 weeks (range: 35-39) and mean age at the time of demise 19.1 days (range: 7-42), showed significant liver injury: infection (n = 7, viral > fungal), congenital malformations (n = 2), and ischemia (n = 1). None had maternal history of gestational alloimmune liver disease (GALD) or previous fetal/neonatal death due to liver failure. Seven of 10 cases (70%) showed EHNRS: pancreas (n = 6), kidneys (n = 4), thyroid and adrenal glands (n = 3), and bronchial glands and heart (n = 2). Iron deposition was most frequent in the pancreas (60%), most diffuse in the kidneys, and seen in at least 2 organs, with pancreas and kidney being the most frequent combination. Hepatic C5b-9 expression was variable (1+ to 4+) except 1 case (100% necrosis). The duration of illness and the mean age at the time of demise tended to be higher in those with EHNRS. In summary, hepatic and EHNRS, with or without C5b-9 expression, are not specific for GALD. Other causes of liver failure should be investigated as clinically and pathologically appropriate.

Acute humoral rejection in an infant without risk factors after heart transplantation.

Graft rejection is the most common factor that limits graft survival after transplantation. During infancy, the humoral immune system is partially suppressed and humoral rejection of a cardiac allograft has not been reported in the absence of risk factors such as prior transplantation, blood transfusions, ventricular assist devices, and elevation of panel reactive antibodies. We present a case of an infant with dilated cardiomyopathy who developed multiple episodes of acute humoral rejection after heart transplantation in the absence of risk factors.

Pre-cannulation lung biopsy shortens ECMO course.

We describe the clinical course of an infant with respiratory failure who underwent lung biopsy prior to cannulation for undergoing extracorporeal membrane oxygenation (ECMO). Pathology revealed alveolar capillary dysplasia, and ECMO was discontinued. Rapid diagnosis allowed for closure and saved resources. We recommend considering early biopsy in infants with atypical pulmonary hypertension.

Pulmonary capillary hemangiomatosis in a neonate with congenital diaphragmatic hernia.

Pulmonary capillary hemangiomatosis (PCH) is a rare cause of pulmonary hypertension (PHTN). We present a neonate with congenital diaphragmatic hernia (CDH) and concurrent PCH. Severe PHTN was unrelenting and death occurred at 4 months. Diagnosis of PCH is challenging in the setting of CDH and portends a poor prognosis.

Molecular basis for clinical heterogeneity in inherited cardiomyopathies due to myopalladin mutations.

Abnormalities in Z-disc proteins cause hypertrophic (HCM), dilated (DCM) and/or restrictive cardiomyopathy (RCM), but disease-causing mechanisms are not fully understood. Myopalladin (MYPN) is a Z-disc protein expressed in striated muscle and functions as a structural, signaling and gene expression regulating molecule in response to muscle stress. MYPN was genetically screened in 900 patients with HCM, DCM and RCM, and disease-causing mechanisms were investigated using comparative immunohistochemical analysis of the patient myocardium and neonatal rat cardiomyocytes expressing mutant MYPN. Cardiac-restricted transgenic (Tg) mice were generated and protein-protein interactions were evaluated. Two nonsense and 13 missense MYPN variants were identified in subjects with DCM, HCM and RCM with the average cardiomyopathy prevalence of 1.66%. Functional studies were performed on two variants (Q529X and Y20C) associated with variable clinical phenotypes. Humans carrying the Y20C-MYPN variant developed HCM or DCM, whereas Q529X-MYPN was found in familial RCM. Disturbed myofibrillogenesis with disruption of α-actinin2, desmin and cardiac ankyrin repeat protein (CARP) was evident in rat cardiomyocytes expressing MYPN(Q529X). Cardiac-restricted MYPN(Y20C) Tg mice developed HCM and disrupted intercalated discs, with disturbed expression of desmin, desmoplakin, connexin43 and vinculin being evident. Failed nuclear translocation and reduced binding of Y20C-MYPN to CARP were demonstrated using in vitro and in vivo systems. MYPN mutations cause various forms of cardiomyopathy via different protein-protein interactions. Q529X-MYPN causes RCM via disturbed myofibrillogenesis, whereas Y20C-MYPN perturbs MYPN nuclear shuttling and leads to abnormal assembly of terminal Z-disc within the cardiac transitional junction and intercalated disc.

Novel FOXF1 mutations in sporadic and familial cases of alveolar capillary dysplasia with misaligned pulmonary veins imply a role for its DNA binding domain.

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV) is a rare and lethal developmental disorder of the lung defined by a constellation of characteristic histopathological features. Nonpulmonary anomalies involving organs of gastrointestinal, cardiovascular, and genitourinary systems have been identified in approximately 80% of patients with ACD/MPV. We have collected DNA and pathological samples from more than 90 infants with ACD/MPV and their family members. Since the publication of our initial report of four point mutations and 10 deletions, we have identified an additional 38 novel nonsynonymous mutations of FOXF1 (nine nonsense, seven frameshift, one inframe deletion, 20 missense, and one no stop). This report represents an up to date list of all known FOXF1 mutations to the best of our knowledge. Majority of the cases are sporadic. We report four familial cases of which three show maternal inheritance, consistent with paternal imprinting of the gene. Twenty five mutations (60%) are located within the putative DNA-binding domain, indicating its plausible role in FOXF1 function. Five mutations map to the second exon. We identified two additional genic and eight genomic deletions upstream to FOXF1. These results corroborate and extend our previous observations and further establish involvement of FOXF1 in ACD/MPV and lung organogenesis.

Expanding the genotype-phenotype correlation in subtelomeric 19p13.3 microdeletions using high resolution clinical chromosomal microarray analysis.

Structural rearrangements of chromosome 19p are rare, and their resulting phenotypic consequences are not well defined. This is the first study to report a cohort of eight patients with subtelomeric 19p13.3 microdeletions, identified using clinical chromosomal microarray analysis (CMA). The deletion sizes ranged from 0.1 to 0.86 Mb. Detailed analysis of the patients' clinical features has enabled us to define a constellation of clinical abnormalities that include growth delay, multiple congenital anomalies, global developmental delay, learning difficulties, and dysmorphic facial features. There are eight genes in the 19p13.3 region that may potentially contribute to the clinical phenotype via haploinsufficiency. Moreover, in silico genomic analysis of 19p13.3 microdeletion breakpoints revealed numerous highly repetitive sequences, suggesting LINEs/SINEs-mediated events in generating these microdeletions. Thus, subtelomeric 19p13.3 appears important for normal embryonic and childhood development. The clinical description of patients with deletions in this genomic interval will assist clinicians to identify and treat individuals with similar deletions.

A 25-year experience of endomyocardial biopsy safety in infants.

OBJECTIVES: To analyze the outcomes and risk factors associated with endomyocardial biopsy (EMB) in children less than one year of age. BACKGROUND: EMB has proven to be an integral diagnostic tool to evaluate suspected myocarditis, identify tumor histology, and provide tissue-graft surveillance after cardiac transplantation. The morbidity and mortality of EMB has been well established in the adult literature and reviewed in the general pediatric population, but there remains limited data for children in the first year of life. METHODS: We retrospectively reviewed the cardiology database at our institution to identify patients less than one year of age who underwent EMB between 1984 and 2008. Cardiac catheterization reports were reviewed for patient demographics, biopsy indication, procedural details, and complications. RESULTS: A total of 99 EMBs were performed, 49 for evaluation of suspected myocarditis, 43 for transplant rejection surveillance, 3 to identify tumor histology, and 4 for suspected endocardial fibroelastosis. Forty procedures were performed in children age < 6 months with 11 complications and 59 procedures performed in children age ≥ 6 months with four complications. In total, there were 12 EMB procedures (12.1%) with associated complications: 9 arrhythmias, 4 perforations requiring pericardiocentesis, 1 pneumothorax, and 1 death. Univariate analysis revealed a significant association between perforation and both weight <8 kg (P = 0.05) and age <6 months (P = 0.01). CONCLUSION: Endomyocardial biopsies can be performed safely in infants, although children under 6 months of age and less than 8 kg represent a high risk group and deserve special consideration due to the incidence of complications in this cohort.

First description of coronary artery ostial atresia with fistulous origin from a normal right ventricle.

Anomalous origins of both the left and right coronary arteries are rare but have been well documented when both arteries arise from the pulmonary trunk (Angelini et al., Circulation 105:2449-2454, 2002). An anomalous coronary arterial origin from the pulmonary arteries usually involves the left coronary artery (ALCPA) and less frequently the right coronary artery (ARCPA). At least three cases have been reported in which the right coronary artery arose abnormally from the left ventricle (LV), but none have been reported in which both coronary arteries took their origin from the right ventricle (Ippisch and Kimball, J Am Soc Echocardiogr 23:222.e1-222.e2, 2010; Okuyama et al., Jpn Heart J 36:115-118, 1995; Culbertson et al., Pediatr Cardiol 16:73-75, 1995). Ostial atresia with anomalous origin of a coronary artery from the right ventricle has been described only in pulmonary atresia with an intact ventricular septum and a hypoplastic right ventricle. In this setting, atresia of both coronary ostia with right ventricular origin of both coronary arteries is a rare variant. This report presents a neonate in whom the entire coronary arterial system arose from the right ventricle via a single fistula with no other intracardiac defects. To the authors' knowledge, this anomaly has not been described previously.

In Utero Presentation of Left Ventricular Aneurysm.

Congenital left ventricular aneurysm, pseudoaneurysm, and diverticulum are rare entities. These diagnoses can be made pre- and/or postnatally. Although these entities overlap clinically and morphologically, important distinctions can allow for accurate diagnoses. Appropriate diagnosis can be imperative for risk stratification and guidance of prenatal and postnatal management. The case described in the present report highlights a challenging case of a fetal left ventricular aneurysm, management during the prenatal and postnatal periods, and important differentiating features from a ventricular diverticulum and pseudoaneurysm.

The Many Faces of Arrhythmogenic Cardiomyopathy: An Overview.

Arrhythmogenic cardiomyopathy (AC) is a disease that involves electromechanical uncoupling of cardiomyocytes. This leads to characteristic histologic changes that ultimately lead to the arrhythmogenic clinical features of the disease. Initially thought to affect the right ventricle predominantly, more recent data show that it can affect both the ventricles or the left ventricle alone. Throughout the recent era, diagnostic modalities and criteria for AC have continued to evolve and our understanding of its clinical features in different age groups as well as the genotype to the phenotype correlations have improved. In this review, we set out to detail the epidemiology, etiologies, presentations, evaluation, and management of AC across the age continuum.

Atypical infiltrates on endomyocardial biopsy are associated with adverse outcomes in pediatric heart transplantation.

BACKGROUND: The significance of atypical infiltrates (eosinophils or plasma cells) on endomyocardial biopsy (EMB) after pediatric heart transplant (HTx) is not known. We hypothesized that atypical infiltrates are associated with worse post-HTx outcomes. METHODS: We performed a retrospective cohort study of consecutive patients <21 years old who underwent primary HTx between 2013 and 2017. Multiorgan transplants were excluded. The presence of atypical infiltrates and burden of atypical infiltrates (rare vs predominant) on EMB were recorded. Primary outcome was a composite of cardiac allograft vasculopathy, graft failure (relisting or retransplant), or death. Presence of atypical infiltrates was evaluated: (1) overall using Cox regression with time-dependent covariates and (2) if present by 1 year post-HTx using Kaplan-Meier analysis. RESULTS: Atypical infiltrates were present in 24 out of 95 patients (25%) and were associated with a higher likelihood of reaching the composite outcome (hazard ratio (HR) 6.22, 95% confidence interval (CI) 2.60-14.89, p < 0.0001). This persisted when controlling for rejection in multivariable analysis. There was also a greater risk of the composite outcome if ≥2 nonconsecutive EMBs had atypical infiltrates (HR 11.80, 95%CI 3.17-43.84, p = 0.0002) or if atypical infiltrates were the predominant feature on EMB (HR 30.58, 95%CI 9.34-100.06, p < 0.0001). Patients with atypical infiltrates by 1-year post-HTx had a 5-year freedom from the composite outcome of 48%, compared to 90% if no atypical infiltrates had been present by this timepoint (log rank p = 0.002). CONCLUSIONS: The presence of atypical infiltrates on EMB is associated with significantly worse outcomes in children following HTx. These patients require closer follow-up to assess for developing graft dysfunction.

Cardiac structural and functional alterations in infants and children with biliary atresia, listed for liver transplantation.

BACKGROUND & AIMS: Cirrhotic liver diseases are associated with abnormalities in cardiac geometry and function in adults (cirrhotic cardiomyopathy) but rarely explored in cirrhotic infants or children. We proposed that features of cirrhotic cardiomyopathy are present in infants with cirrhosis due to biliary atresia (BA) as early as the time of evaluation for liver transplant and will correlate with mortality and postoperative morbidity. METHODS: Two-dimensional echocardiography (2DE) of infants with BA (n=40; median age, 8 months), listed for transplantation at the Texas Children's Hospital from 2004 to 2010, were reviewed and compared with age- and sex-matched infants without cardiac or liver disease (controls). Length of stay and correlation with 2DE results were assessed. RESULTS: Compared with controls, children with BA had significant increases in multiple 2DE parameters, notably left ventricle wall thickness (23% increase), left ventricular (LV) mass indexed to body surface area (51% increase), and LV shortening fraction (8% increase). Overall, features of cirrhotic cardiomyopathy were observed in most infants (29/40; 72%); 17 had hyperdynamic contractility, and 24 had altered LV geometry. After liver transplantation (33), infants with abnormal 2DE results had longer stays in the intensive care unit (median, 6 vs 4 days) and the hospital (21 vs 11 days) compared with infants who had normal 2DE reports. On univariate analysis, the length of hospital stay correlated with LV mass index. CONCLUSIONS: Cardiomyopathy is a prevalent condition in infants with end-stage cirrhotic liver disease due to BA (>70%). This underrecognized condition likely contributes to the prolongation of posttransplant hospitalization.

Congenital Aortic Insufficiency From an Abnormal Left Aortic Cusp Results in Acute Coronary Syndrome.

Acute coronary syndrome (ACS) is a rare presentation in children with isolated congenital aortic insufficiency (AI). We report the case of a six-week-old previously well male who presented with an out-of-hospital cardiac arrest and was diagnosed with severe AI from a left aortic cusp anomaly resulting in ACS. The infant successfully underwent an emergent Ross operation.

A Novel Large-Vessel Arteritis in SARS-CoV-2-Related Multisystem Inflammatory Syndrome in Children (MIS-C).

Multisystem inflammatory syndrome in children (MIS-C) is a newly defined condition associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The syndrome has been described as a "Kawasaki disease"-like illness and the spectrum of associated abnormalities, including vascular complications, remain to be fully defined. The novel findings of a large-vessel arteritis in this report will add to the understanding of this syndrome and its associated vascular complications.

Elevation of RNA-binding protein CUGBP1 is an early event in an inducible heart-specific mouse model of myotonic dystrophy.

Myotonic dystrophy type 1 (DM1) is caused by a CTG trinucleotide expansion in the 3' untranslated region (3' UTR) of DM protein kinase (DMPK). The key feature of DM1 pathogenesis is nuclear accumulation of RNA, which causes aberrant alternative splicing of specific pre-mRNAs by altering the functions of CUG-binding proteins (CUGBPs). Cardiac involvement occurs in more than 80% of individuals with DM1 and is responsible for up to 30% of disease-related deaths. We have generated an inducible and heart-specific DM1 mouse model expressing expanded CUG RNA in the context of DMPK 3' UTR that recapitulated pathological and molecular features of DM1 including dilated cardiomyopathy, arrhythmias, systolic and diastolic dysfunction, and mis-regulated alternative splicing. Combined in situ hybridization and immunofluorescent staining for CUGBP1 and CUGBP2, the 2 CUGBP1 and ETR-3 like factor (CELF) proteins expressed in heart, demonstrated elevated protein levels specifically in nuclei containing foci of CUG repeat RNA. A time-course study demonstrated that colocalization of MBNL1 with RNA foci and increased CUGBP1 occurred within hours of induced expression of CUG repeat RNA and coincided with reversion to embryonic splicing patterns. These results indicate that CUGBP1 upregulation is an early and primary response to expression of CUG repeat RNA.

Refractory dilated cardiomyopathy associated with metastatic neuroblastoma.

A 2-year-old African American male presented with heart failure and an abdominal mass. Computerized tomography (CT) scan revealed a 7 cm adrenal lesion, confirmed as poorly differentiated neuroblastoma (NB). CT and meta-iodobenzoguanidine (MIBG) scans identified multiple metastases, but cardiac MIBG imaging was absent. Cardiac ejection fraction (EF) was 8% with 7% shortening fraction. The patient underwent six cycles of chemotherapy and investigational immunotherapy. Cardiac function improved to 26% EF. However, the tumor proved unresponsive to treatment. The patient died from stage IV congestive heart failure (CHF) and progressive NB. Autopsy confirmed dilated cardiomyopathy with endocardial fibroelastosis.