Myocarditis-A Helpful Algorithm to Overcome Diagnostic Challenges in the Pediatric Population.

OBJECTIVES: This study was designed to investigate clinical differences between pediatric patients who presented with chest pain, tachycardia, and/or tachypnea who subsequently were or were not diagnosed with myocarditis. The results were used to develop a decision tree to aid in rapid diagnosis of pediatric myocarditis. METHODS: A retrospective case-control study was performed using the electronic medical records of children aged 0 to 18 years between the years 2003 and 2020 with a complaint of chest pain, tachycardia, and/or tachypnea. Patients included in the study were those diagnosed with myocarditis and those with suspected myocarditis, which was ultimately ruled out. Demographic and clinical differences between the research groups were analyzed. A decision tree was rendered using the rpart (Recursive Partitioning and Regression Trees) package. RESULTS: Four thousand one hundred twenty-five patients were screened for eligibility. Seventy-three myocarditis patients and 292 nonmyocarditis patients were included. Compared with the control group, the study group was found to have a higher mean respiratory rate (37 ± 23 vs 23 ± 7 breaths per minute) and mean heart rate (121 ± 44 vs 97 ± 25 beats per minute) and lower mean systolic and diastolic blood pressure (102 ± 27/56 ± 17 mm Hg vs 114 ± 14/67 ± 10 mm Hg). The mean white blood cell count was greater in the case group (13 ± 6 vs 10 ± 5 × 10 3 /µL). A decision tree was rendered using simple demographic and clinical variables. The accuracy of the algorithm was 85.2%, with 100% accuracy in patients aged 0 to 2.5 years and 69% in patients aged 2.5 to 18 years. CONCLUSION: The clinical and laboratory characteristics described in this study were similar to what is described in the literature. The decision tree may aid in the diagnosis of myocarditis in patients 2.5 years and younger. In the population aged 2.5 to 18 years, the decision tree did not constitute an adequate tool for detecting myocarditis.

A Novel Mutation in the ADAMTS10 Associated with Weil-Marchesani Syndrome with a Unique Presentation of Developed Membranes Causing Severe Stenosis of the Supra Pulmonic, Supramitral, and Subaortic Areas in the Heart.

Weill-Marchesani syndrome (WMS) is a rare genetic inherited disorder with autosomal recessive and dominant modes of inheritance. WMS is characterized by the association of short stature, brachydactyly, joint stiffness, eye anomalies, including microspherophakia and ectopia of the lenses, and, occasionally, heart defects. We investigated the genetic cause of a unique and novel presentation of heart-developed membranes in the supra-pulmonic, supramitral, and subaortic areas, creating stenosis that recurred after their surgical resection in four patients from one extended consanguineous family. The patients also presented ocular findings consistent with Weill-Marchesani syndrome (WMS). We used whole exome sequencing (WES) to identify the causative mutation and report it as a homozygous nucleotide change c. 232T>C causing p. Tyr78His in ADAMTS10. ADAMTS10 (ADAM Metallopeptidase with Thrombospondin Type 1 Motif 10) is a member of a family of zinc-dependent extracellular matrix protease family. This is the first report of a mutation in the pro-domain of ADAMTS10. The novel variation replaces a highly evolutionary conserved tyrosine with histidine. This change may affect the secretion or function of ADAMTS10 in the extracellular matrix. The compromise in protease activity may thus cause the unique presentation of the developed membranes in the heart and their recurrence after surgery.

A Missense Variation in PHACTR2 Associates with Impaired Actin Dynamics, Dilated Cardiomyopathy, and Left Ventricular Non-Compaction in Humans.

Dilated cardiomyopathy (DCM) with left ventricular non-compaction (LVNC) is a primary myocardial disease leading to contractile dysfunction, progressive heart failure, and excessive risk of sudden cardiac death. Using whole-exome sequencing to investigate a possible genetic cause of DCM with LVNC in a consanguineous child, a homozygous nucleotide change c.1532G>A causing p.Arg511His in PHACTR2 was found. The missense change can affect the binding of PHACTR2 to actin by eliminating the hydrogen bonds between them. The amino acid change does not change PHACTR2 localization to the cytoplasm. The patient's fibroblasts showed a decreased globular to fibrillary actin ratio compared to the control fibroblasts. The re-polymerization of fibrillary actin after treatment with cytochalasin D, which disrupts the actin filaments, was slower in the patient's fibroblasts. Finally, the patient's fibroblasts bridged a scar gap slower than the control fibroblasts because of slower and indirect movement. This is the first report of a human variation in this PHACTR family member. The knock-out mouse model presented no significant phenotype. Our data underscore the importance of PHACTR2 in regulating the monomeric actin pool, the kinetics of actin polymerization, and cell movement, emphasizing the importance of actin regulation for the normal function of the human heart.

CAP2 mutation leads to impaired actin dynamics and associates with supraventricular tachycardia and dilated cardiomyopathy.

BACKGROUND: Dilated cardiomyopathy (DCM) is a primary myocardial disease leading to contractile dysfunction, progressive heart failure and excessive risk of sudden cardiac death. Around half of DCM cases are idiopathic, and genetic factors seem to play an important role. AIM: We investigated a possible genetic cause of DCM in two consanguineous children from a Bedouin family. METHODS AND RESULTS: Using exome sequencing and searching for rare homozygous variations, we identified a nucleotide change in the donor splice consensus sequence of exon 7 in CAP2 as the causative mutation. Using patient-derived fibroblasts, we demonstrated that the mutation causes skipping of exons 6 and 7. The resulting protein is missing 64 amino acids in its N-CAP domain that should prevent its correct folding. CAP2 protein level was markedly reduced without notable compensation by the homolog CAP1. However, ß-actin mRNA was elevated as demonstrated by real-time qPCR. In agreement with the essential role of CAP2 in actin filament polymerization, we demonstrate that the mutation affects the kinetics of repolymerization of actin in patient fibroblasts. CONCLUSIONS: This is the first report of a recessive deleterious mutation in CAP2 and its association with DCM in humans. The clinical phenotype recapitulates the damaging effects on the heart observed in Cap2 knockout mice including DCM and cardiac conduction disease, but not the other effects on growth, viability, wound healing and eye development. Our data underscore the importance of the proper kinetics of actin polymerization for normal function of the human heart.

Recombinant tissue plasminogen activator as a novel treatment option for infective endocarditis: a retrospective clinical study in 32 children.

Infective endocarditis is a life-threatening infectious syndrome, with high morbidity and mortality. Current treatments for infective endocarditis include intravenous antibiotics, surgery, and involve a lengthy hospital stay. We hypothesised that adjunctive recombinant tissue plasminogen activator treatment for infective endocarditis may facilitate faster resolution of vegetations and clearance of positive blood cultures, and therefore decrease morbidity and mortality. This retrospective study included follow-up of patients, from 1997 through 2014, including clinical presentation, causative organism, length of treatment, morbidity, and mortality. We identified 32 patients, all of whom were diagnosed with endocarditis and were treated by recombinant tissue plasminogen activator. Among all, 27 patients (93%) had positive blood cultures, with the most frequent organisms being Staphylococcus epidermis (nine patients), Staphylococcus aureus (six patients), and Candida (nine patients). Upon treatment, in 31 patients (97%), resolution of vegetations and clearance of blood cultures occurred within hours to few days. Out of 32 patients, one patient (3%) died and three patients (9%) suffered embolic or haemorrhagic events, possibly related to the recombinant tissue plasminogen activator. None of the patients required surgical intervention to assist vegetation resolution. In conclusion, it appears that recombinant tissue plasminogen activator may become an adjunctive treatment for infective endocarditis and may decrease morbidity as compared with current guidelines. Prospective multi-centre studies are required to validate our findings.

Duchenne Muscular Dystrophy and Early Onset Hypertrophic Cardiomyopathy associated with Mutations in Dystrophin and Hypertrophic Cardiomyopathy-Associated Genes.

Duchenne muscular dystrophy (DMD) is a progressive muscular damage disorder caused by mutations in dystrophin gene. Cardiomyopathy may first be evident after 10 years of age and increases in incidence with age. We present a boy diagnosed at 18 months with a rare phenotype of DMD in association with early-onset hypertrophic cardiomyopathy (HCM). The cause of DMD is a deletion of exons 51-54 of dystrophin gene. The cause of HCM was verified by whole exome sequencing. Novel missense variations in two genes: MAP2K5 inherited from the mother and ACTN2 inherited from the father, or de novo. The combination of MAP2K5 , ACTN2 , and dystrophin mutations, could be causing the HCM in our patient. This is the second patient diagnosed, at relatively young age, with DMD and HCM, with novel variations in genes known to cause HCM. This study demonstrates the need for genetic diagnosis to elucidate the underlying pathology of HCM.

Cesarean section and the risk of fractured femur.

BACKGROUND: The rate of cesarean section is increasing and in the United States recently exceeded 30% of all deliveries. Birth injuries during CS are relatively rare. Femur fractures have a very low incidence during both vaginal delivery and CS. OBJECTIVES: To assess our 10 year experience (2008-1997) in managing fractured femur during CS, including a typical case. METHODS: We reviewed the prevalence of femur fractures in two tertiary, academic, level one trauma center hospitals in Israel (Hadassah in Jerusalem and Soroka in Beer Sheva). RESULTS: During the study period 221,939 deliveries occurred in both hospitals. Of these, 17.6% were cesarean sections (38,990 CS). Of the total number of deliveries, the incidence of femur fracture was 0.077 per 1000 deliveries (17 fractures), and the incidence of femur fracture during CS was 0.308 per 1000 CS (12 fractures). CONCLUSIONS: Cesarean section increases the risk of femur fractures (P < 0.001) with an odds ratio of 11.26 (confidence interval 3.97-31.97).

Streptobacillus moniliformis Endocarditis: An Unusual Case of Pulmonary Valve Erosion Resulting in Free Pulmonary Regurgitation and Aneurysm.

Endocarditis is a consideration in the differential diagnosis when masses are seen on echocardiography in a patient with congenital heart disease. We present a case of insidious development of endocarditis caused by Streptobacillus moniliformis in a seven-month-old baby after a rat bite, when the baby was three months of age.

Risk factors for recurrent preterm delivery.

OBJECTIVE: To identify risk factors for recurrent preterm delivery among primiparous women with previous preterm delivery. STUDY DESIGN: A retrospective case-control study was designed: 152 primiparous women who delivered preterm (22-36 weeks) were divided into two groups: 81 had a second preterm delivery (study group) and 71 had a second-term delivery (control group). Exclusion criteria were induced preterm delivery, hydramnions and multiple gestations. RESULTS: Comparing second preterm delivery before 34 weeks (n = 36) to the second delivery of the control group, higher rates of hospitalization due to preterm labor were noted in the study versus the control group (52.8% versus 16.9%,P = 0.001). The interval between pregnancies was shorter in the study subgroup, before 34 weeks gestational age, versus the controls (20.1 +/-15.7 months versus 28.9 +/- 18.7 months, P = 0.011). Multiple regression analyses, adjusted for confounding variables, found the occurrence of preterm labor and short interval between pregnancies, especially up to 12 months, as independent risk factors for the recurrence of preterm delivery (OR = 4.98; P , 0.001; OR = 5.13; P = 0.007, respectively). CONCLUSION: When adjusted for confounding variables, short interval between pregnancies is an independent risk factor for recurrent preterm delivery.

Transient severe metastatic calcification in acute renal failure.

Metastatic calcification, a known complication of prolonged end-stage renal disease, is herein described for the first time in a 10-month-old boy with acute renal failure, manifesting as a painful and swollen arm. Imaging revealed diffuse calcification and technetium-99 methylene diphosphonate (99Tc-MDP) uptake around the humerus and axilla. Calcium and vitamin D restriction, followed by intravenous administration of sodium thiosulfate caused a full symptomatic, radio- and scintigraphic improvement.