Evaluation of Risk for Thromboembolic Events in Pediatric Inflammatory Bowel Disease.

OBJECTIVES: The occurrence of thrombotic events in adult patients with inflammatory bowel disease (IBD) is linked to multiple interactions between hereditary and acquired risk factors. There are few published data concerning children with iBD. The aim of this study was to investigate the presence of thromboembolic risk factors also in children with iBD. METHODS: We enrolled three groups of children: one with Crohn disease (cD), one with ulcerative colitis (Uc), and a control group of healthy subjects. For all the participants the potential thromboembolic risk was evaluated clinically and with laboratory tests. RESULTS: We studied: 30 children (25.6%) with CD, 28 (23.9%) with UC, and 59 (50.4%) healthy control subjects. Regarding Pediatric Crohn Disease Activity Index, no significant differences between thromboembolic risk factors and disease activity were detected. Instead, in the patients with UC, stratified with the Pediatric Ulcerative Colitis Activity Index, there was a statistically significant difference in serum fibrinogen levels between patients with mild and moderate/severe disease [3.8 (3.2-4.5) g/L vs 5.7 (4.8-6.2) g/L, P  < 0.0032]. serum homocysteine levels were lower in healthy controls than in CD (P = 0.176) and UC (P = 0.026). An increased level ofhomocysteine in UC with a homozygous mutation in the methylene tetrahydrofolate reductase C677T gene was also observed. CONCLUSIONS: Our study showed that children with IBD have clinical features, acquired and congenital factors that can increase thrombotic risk, similarly to adults.

Comparing parental distress and children's difficulties between parents of children with rheumatic diseases and parents of healthy children in families facing the COVID-19 pandemic.

The COVID-19 pandemic could be a threat for the health status of children with a chronic condition. The present study aimed to explore parents' and children's psychological adjustment during the current pandemic, pursuing a triple objective: to compare the psychological adjustment of parents of children with pediatric rheumatic diseases (PRDs) and parents of healthy children; to analyze children's psychological symptoms (emotional problems and hyperactivity) before and during the COVID-19 pandemic, and with or without a PRDs diagnosis; to explore the associations of children's emotional problems and hyperactivity with parents' psychological adjustment, parent-child interactions and belonging or not to families with PRDs. This cross-sectional study involved 56 parents of children with PRDs and 53 parents of healthy children. Self-report questionnaires about parents' depression, anxiety, parenting stress, and children's emotional symptoms and hyperactivity-inattention were administered. No differences were detected on psychological adjustment between parents of children with PRDs and parents of healthy children. Parents of children with PRDs reported statistically significant higher levels of children's emotional problems and hyperactivity before the pandemic, compared to parents of healthy children; during COVID-19 pandemic, emotional symptoms increased for both groups, while hyperactivity-inattention symptoms increased only in the group of healthy children. Children's emotional difficulties were associated with higher levels of parental anxiety, worse parent-child interaction and having PRDs; children's hyperactivity symptoms were related to parent-child difficult interaction and higher levels of parental depression. Findings suggest the importance to target the children in relation to their parents, when approaching the psychological aspects of PRDs.

External hydrocephalus as a prenatal feature of noonan syndrome.

Brain malformations have been reported in RASopathies, including postnatal external hydrocephalus, a nonobstructive form of cerebrospinal fluid accumulation around the brain. It was described in a few patients with mutations of other genes than PTPN11, such as SOS1 and SHOC2 and never in prenatal diagnosis. The aim of this case report is to describe the prenatal presentation of a fetus with Noonan syndrome (NS) and external hydrocephalus. We report on a Noonan syndrome fetus with a de novo pathogenic PTPN11 c.923A>G p.Asn308Ser mutation, showing external hydrocephalus, an extremely rare fetal finding, corpus callosum, and cerebellar vermis under the 10th centile, plus a typical NS cardiopathy. This is the first case of Noonan syndrome prenatal diagnosis in a fetus presenting with external hydrocephalus. Following pathophysiological considerations, we suggest to consider NS in the differential diagnosis of external hydrocephalus, investigating other evocative findings and considering molecular screening for mutations in NS-related genes.

Effects of N95 Mask Use on Pulmonary Function in Children.

OBJECTIVE: To assess whether use of an N95 mask by children is associated with episodes of desaturation or respiratory distress. STUDY DESIGN: Twenty-two healthy children were assigned at random to 1 of 2 groups: one group wearing N95 masks without an exhalation valve and the other group wearing N95 masks with an exhalation valve. We tracked changes in partial pressure of end-tidal carbon dioxide (PETCO2), oxygen saturation, pulse rate, and respiratory rate over 72 minutes of mask use. All subjects were monitored every 15 minutes, the first 30 minutes while not wearing a mask and the next 30 minutes while wearing a mask. They then performed a 12-minute walking test. RESULTS: The children did not experience a statistically significant change in oxygen saturation or pulse rate during the study. There were significant increases in respiratory rate and PETCO2 in the children wearing an N95 mask without an exhalation valve, whereas these increases were seen in the children wearing a mask with an exhalation valve only after the walking test. CONCLUSIONS: The use of an N95 mask could potentially cause breathing difficulties in children if the mask does not have an exhalation valve, particularly during a physical activity. We believe that wearing a surgical mask may be more appropriate for children.

The comprehensive clinic, laboratory, and instrumental evaluation of children with COVID-19: A 6-months prospective study.

OBJECTIVES: To perform a comprehensive clinic, laboratory, and instrumental evaluation of children affected by coronavirus disease (COVID-19). METHODS: Children with a positive result of nasopharyngeal swab for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) underwent laboratory tests, anal and conjunctival swab, electrocardiography, lung, abdomen, and cardiac ultrasound. Twenty-four-hour ambulatory blood pressure monitoring was performed if abnormal basal blood pressure. Patients were followed-up for 6 months. RESULTS: Three hundred and sixteen children were evaluated; 15 were finally included. Confirmed family member SARS-CoV-2 infection was present in all. Twenty-seven percent were asymptomatic. Anal and conjunctival swabs tests resulted negative in all. Patients with lower body mass index (BMI) presented significantly higher viral loads. Main laboratory abnormalities were: lactate dehydrogenase increasing (73%), low vitamin D levels (87%), hematuria (33%), proteinuria (26%), renal hyperfiltration (33%), and hypofiltration (13%). Two of the patients with hyperfiltration exhibited high blood pressure levels at diagnosis, and persistence of prehypertension at 6-month follow-up. No abnormalities were seen at ultrasound, excepting for one patient who exhibited B-lines at lung sonography. Immunoglobulin G seroconversion was observed in all at 1-month. CONCLUSIONS: Our study confirm that intra-family transmission is important. The significant higher viral loads recorded among patients with lower BMI, together with low vitamin D levels, support the impact of nutritional status on immune system. Renal involvement is frequent even among children with mild COVID-19, therefore prompt evaluation and identification of patients with reduced renal function reserve would allow a better stratification and management of patients. Seroconversion occurs also in asymptomatic children, with no differences in antibodies titer according to age, sex and clinical manifestations.

Serum IgG levels in children 6 months after SARS-CoV-2 infection and comparison with adults.

Since the outbreak of SARS-CoV-2 among the population has occurred quite recently, there is a lack of evidence on the long-term duration of antibody response, especially in children. It is therefore crucial to clarify this aspect, considering its implications in the development of successful surveillance strategies, therapies, and vaccinations. The aim of this study was to assess the antibody response in a children group after SARS-CoV-2 infection, and to compare it with that of their parents affected by SARS-CoV-2 infection. We enrolled 12 children and their parents, both groups being affected by COVID-19 in April 2020. In the children's group, we collected real-time RT-PCR cycle threshold (Ct) values and gene characterization of first nasal-throat swab at the time of diagnosis (T0); 30 days after the diagnosis (T30), we performed blood tests to detect anti-SARS-CoV-2 IgM and IgG. Finally, 180 days after the diagnosis (T180), we measured anti-SARS-CoV-2 IgG in both children and parents. In children, antibody levels declined significantly at 180 days (T180) after first measurement (T30). There were no significant differences in IgG level related to age, sex, and clinical manifestations. We found a significant correlation between IgG titers at T30 and Ct value of gene N. Children showed a lower level of antibodies against SARS-CoV-2 at T180 compared to their parents.Conclusion: Antibody responses in children waned 180 days after SARS-CoV-2 infection, and at the same time, their parents showed a different antibody response to the virus. These results highlight that serological tests should be used with caution in surveillance strategies among the general population. What is known: • Currently is not known how long antibody response will be maintained or if it protects from reinfection. • Recent reports in adults suggest that antibodies to SARS-CoV-2 declined several months after infection, but data are missing in pediatric age. What is new: • We showed that antibody responses to SARS-CoV-2 wane several months after infection also in children with quantitative differences in antibody levels between children and adults. • In this context, serological tests should be used with caution in surveillance strategies.

Clinical and functional characterization of a novel RASopathy-causing SHOC2 mutation associated with prenatal-onset hypertrophic cardiomyopathy.

SHOC2 is a scaffold protein mediating RAS-promoted activation of mitogen-activated protein kinase (MAPK) signaling in response to extracellular stimuli. A recurrent activating mutation in SHOC2 (p.Ser2Gly) causes Mazzanti syndrome, a RASopathy characterized by features resembling Noonan syndrome and distinctive ectodermal abnormalities. A second mutation (p.Met173Ile) supposed to cause loss-of-function was more recently identified in two individuals with milder phenotypes. Here, we report on the third RASopathy-causing SHOC2 mutation (c.807_808delinsTT, p.Gln269_His270delinsHisTyr), which was found associated with prenatal-onset hypertrophic cardiomyopathy. Structural analyses indicated a possible impact of the mutation on the relative orientation of the two SHOC2's leucine-rich repeat domains. Functional studies provided evidence of its activating role, revealing enhanced binding of the mutant protein to MRAS and PPP1CB, and increased signaling through the MAPK cascade. Differing from SHOC2 S2G , SHOC2 Q269_H270delinsHY is not constitutively targeted to the plasma membrane. These data document that diverse mechanisms in SHOC2 functional dysregulation converge toward MAPK signaling upregulation.

Giant right atrium and subvalvular pulmonary stenosis: A case report of an interesting combination.

A 20-year-old Congolese woman presented with presyncope, dyspnea, and anasarca. Past medical history was unremarkable. Echocardiography revealed a rare combination of giant right atrium (RA), a dilated and hypertrophied right ventricle, subvalvular pulmonary stenosis (subPS), severe tricuspid regurgitation (TR), pericardial effusion and what appeared to be a spontaneously closed ventricular septal defect (VSD). Cardiac Magnetic Resonance and Cardiac Computed Tomography confirmed the findings excluding the presence of intra-cardiac and extra-cardiac shunt and other associated congenital anomalies. The patient underwent subPS resection, right atrioplasty, and tricuspid annuloplasty. Multimodality approach facilitated the detection of the abnormalities and provided clarity when determining the optimal surgical strategy.

Congenital jugular vein phlebectasia or aneurysma: A rare entity in prenatal diagnosis.

Vascular malformations arising from the wall of the external jugular vein are rare and appeared most commonly in pediatric population. Here, we present a case of vascular malformation in the left external jugular vein diagnosed in a fetus during third trimester ultrasound. This is the first described case in prenatal diagnosis.

Epirubicin: a new entry in the list of fetal cardiotoxic drugs? Intrauterine death of one fetus in a twin pregnancy. Case report and review of literature.

BACKGROUND: Current knowledge indicate that epirubicin administration in late pregnancy is almost devoid of any fetal cardiotoxicity. We report a twin pregnancy complicated by breast cancer in which epirubicin administration was causatively linked to the death of one twin who was small for gestational age (SGA) and in a condition of oligohydramnios and determined the onset of a transient cardiotoxicity of the surviving fetus/newborn. CASE PRESENTATION: A 38-year-old caucasic woman with a dichorionic twin pregnancy was referred to our center at 20 and 1/7 weeks for a suspected breast cancer, later confirmed by the histopathology report. At 31 and 3/7 weeks, after the second chemotherapy cycle, ultrasound examination evidenced the demise of one twin while cardiac examination revealed a monophasic diastolic ventricular filling, i.e. a diastolic dysfunction of the surviving fetus who was delivered the following day due to the occurrence of grade II placental abruption. The role of epirubicin cardiotoxicity in the death of the first twin was supported by post-mortem cardiac and placental examination and by the absence of structural or genomic abnormalities that may indicate an alternative etiology of fetal demise. The occurrence of epirubicin cardiotoxicity in the surviving newborn was confirmed by the report of high levels of troponin and transient left ventricular septal hypokinesia. CONCLUSION: Based on our findings we suggest that epirubicin administration in pregnancy should be preceded by the screening of some fetal conditions like SGA and oligohydramnios that may increase its cardiotoxicity and that, during treatment, the diastolic function of the fetal right ventricle should be specifically monitored by a pediatric cardiologist; also, epirubicin and desamethasone for lung maturation should not be closely administered since placental effects of glucocorticoids may increase epirubicin toxicity.

Double aortic arch: postnatal obliteration of the left aortic arch. Is arterial duct closure responsible?

We present a case of double aortic arch with a predominant right and a double arterial duct detected by echocardiogram in a 28-week gestation foetus. The first evaluation revealed that both arches were perfused; the 1-month postnatal echocardiogram showed the closure of both arterial ducts and the partial obliteration of the left aortic arch between the left subclavian artery and the dorsal aorta. In our case, the postnatal obliteration of the left arch in a double aortic arch was probably due to the closure of the left-sided arterial duct.

Proteinuria and hematuria as early signs of renal involvement in juvenile idiopathic arthritis.

Objectives: To evaluate glomerular and tubular renal functions and analyze blood pressure in a cohort of pediatric patients with juvenile idiopathic arthritis (JIA). Methods: A total of 40 pediatric patients, 20 (50%) with JIA and 20 (50%) healthy control subjects, were studied, and performed the renal function on 24-h collection and the 24-h ambulatory blood pressure monitoring (ABPM). Moreover, we compared renal function and blood pressure trends between the groups of JIA patients with different disease activities. Results: No statistically significant differences were observed between patients with JIA and healthy children in terms of glomerular filtration rate (GFR), fractional excretion of sodium (FENa), tubular reabsorption of phosphate (TRP), and calcium-creatinine urine ratio (CaU/CrU). In contrast, we observed significantly higher values in JIA patients than in controls for the presence of hematuria (p < 0.0001) and proteinuria (p < 0.0001). Compared to the control group there were significantly higher values of hematuria and proteinuria/day in both groups of JIA patients with low disease activity (respectively, p = 0.0001 and p = 0.0002) and moderate disease activity (respectively p = 0.0001 and p = 0.0012). Systolic and diastolic dipping were significantly reduced in patients with JIA compared with healthy controls (p < 0.0001 and p < 0.0001, respectively). Conclusions: Our study showed that children with JIA, already in the early stages of the disease, have higher values of hematuria and proteinuria, which are early warning signs of nephropathy. Therefore, detailed screening of renal function and pressure monitoring in patients are necessary to monitor their evolution over time.

Emergency Department Admissions of Children with Chest Pain before and during COVID-19 Pandemic.

OBJECTIVES: We compared the number of accesses, causes, and instrumental evaluations of chest pain in children between the pre-COVID-19 era and the COVID-19 period and analyzed the assessment performed in children with chest pain, highlighting unnecessary examinations. METHODS: We enrolled children with chest pain admitted to our emergency department between January 2019 and May 2021. We collected demographic and clinical characteristics and findings on physical examinations, laboratory tests, and diagnostic evaluations. Then, we compared the number of accesses, causes, and instrumental assessments of chest pain between the pre-COVID-19 era and the COVID-19 era. RESULTS: A total of 111 patients enrolled (mean age: 119.8 ± 40.48 months; 62 males). The most frequent cause of chest pain was idiopathic (58.55%); we showed a cardiac origin in 4.5% of the cases. Troponin determination was performed in 107 patients, and the value was high only in one case; chest X-rays in 55 cases and echocardiograms in 25 cases showed pathological findings, respectively, in 10 and 5 cases. Chest pain accesses increased during the COVID-19 era (p < 0.0001), with no differences in the causes of chest pain between the two periods. CONCLUSIONS: The increase in accesses for chest pain during the COVID-19 pandemic confirms that this symptom generates anxiety among parents. Furthermore, our findings demonstrate that the evaluation of chest pain is still extensive, and new chest pain assessment protocols in the pediatric age group are needed.

Prenatal CFAP53-related laterality defect: case report and review of the literature.

Laterality defects include morphological anomalies with impaired left-right asymmetry induction, such as dextrocardia, situs inversus abdominis, situs inversus totalis and situs ambiguus. The different arrangement of major organs is called heterotaxy. We describe for the first time a fetus with situs viscerum inversus and azygos continuation of the inferior vena cava, due to previously unreported variants in compound heterozygosity in the CFAP53 gene, whose product is implied in cilial motility. Prenatal trio exome sequencing was performed with turn-around time during the pregnancy. The fetuses with laterality defects are suitable candidates for prenatal exome sequencing due to the emerging high diagnostic rate of this group of morphological anomalies. A timely molecular diagnosis plays a fundamental role in genetic counseling, regarding couple decisions on the ongoing pregnancy, providing recurrence risks, and in predicting possible respiratory complications due to ciliary dyskinesia.

Efficacy of Burosumab Every 2 Weeks in an Adult with X-Linked Hypophosphatemia: Should We Learn from Children?

X-linked hypophosphatemia is a genetic condition that leads to fibroblast-growth-factor 23 (FGF23) increase, causing phosphate renal wasting. Since 2018, burosumab, an anti-FGF23 antibody, has been used for this disease with different dosage in children and adults. We report the case of burosumab administration every 2 weeks, as usually done in children. We retrospectively evaluated parathormone (PTH), alkaline phosphatase, serum phosphate, tubular reabsorption of phosphate (TRP), and 25OH vitamin D every 2 weeks in a 29-year-old man with nephrocalcinosis and tertiary hyperparathyroidism who did not respond to standard treatment with burosumab nor to maximum dosage and was treated with burosumab 90 mg every 2 weeks. His serum phosphate and TRP increased with this regimen compared with 4 weeks frequency (respectively 1.74 ± 0.26 mg/dL vs. 2.3 ± 0.19 mg/dL [p 0.0004] and 71.3% ± 4.8% vs. 83.9% ± 7.9% [p 0.01]) with decrease in PTH (183 ± 24.7 pg/mL vs. 109 ± 12.2 pg/mL [p 0.04]). Burosumab may be a good choice in adult patients with X-linked hypophosphatemia; new data are needed regarding the increase in dosage and/or frequency of administration as usually done in children, to achieve disease control.

Post-Infectious Acute Cerebellar Ataxia Treatment, a Case Report and Review of Literature.

BACKGROUND: infectious mononucleosis is very common during childhood and neurological manifestations are extremely rare. However, when they occur, an appropriate treatment must be undertaken to reduce morbidity and mortality as well as to ensure appropriate management. METHODS: we describe the clinical and neurological records of a female patient with post-EBV acute cerebellar ataxia, whose symptoms rapidly resolved with intravenous immunoglobulin therapy. Afterwards, we compared our results with published data. RESULTS: we reported the case of an adolescent female with a 5-day history of sudden asthenia, vomiting, dizziness, and dehydration, with a positive monospot test and hypertransaminasemia. In the following days, she developed acute ataxia, drowsiness, vertigo, and nystagmus with a positive EBV IgM titer, confirming acute infectious mononucleosis. The patient was clinically diagnosed with EBV-associated acute cerebellitis. A brain MRI showed no acute changes and a CT scan showed hepatosplenomegaly. She started therapy with acyclovir and dexamethasone. After a few days, because of her condition's deterioration, she received intravenous immunoglobulin and demonstrated a good clinical response. CONCLUSIONS: although there are no consensus guidelines for the treatment of post-infectious acute cerebellar ataxia, early intervention with intravenous immunoglobulin might prevent adverse outcomes, especially in cases that do not respond to high-dose steroid therapy.

Point-of-Care Thoracic Ultrasound in Children: New Advances in Pediatric Emergency Setting.

Point-of-care thoracic ultrasound at the patient's bedside has increased significantly recently, especially in pediatric settings. Its low cost, rapidity, simplicity, and repeatability make it a practical examination to guide diagnosis and treatment choices, especially in pediatric emergency departments. The fields of application of this innovative imaging method are many and include primarily the study of lungs but also that of the heart, diaphragm, and vessels. This manuscript aims to describe the most important evidence for using thoracic ultrasound in the pediatric emergency setting.

Facing Pediatric Rheumatic Diseases: The Role of Disease Activity and Parental Emotion Regulation Strategy in Parents' and Children's Psychological Adjustment.

BACKGROUND: Pediatric rheumatic diseases (PRDs) are a group of chronic disorders that start in childhood and are characterized by periodic exacerbations and remissions of symptoms, with limitations in family, school, and social activities. The aim of this study was to detect differences in parents' psychological adjustment and emotion regulation strategies, and parent-reported children's adjustments in families of children with active and inactive PRDs. METHODS: Fifty-four parents (38 mothers and 16 fathers) of children with PRD were recruited from a pediatric unit. Disease activity was evaluated by their pediatric rheumatologist, while parents' depressive and anxiety symptoms, emotion regulation strategies, and children's emotional difficulties and hyperactivity-inattention symptoms were assessed through a web-based survey. RESULTS: Parents of children with active PRDs reported higher levels of their child's emotional difficulties and hyperactivity-inattention symptoms. Linear regression analysis demonstrated that having a child in the active phases of PRD and lower use of cognitive reappraisal lead to higher children's emotional symptoms, while active disease, low use of cognitive reappraisal, and greater expressive suppression were associated with higher hyperactivity-inattention symptoms. Our study highlights that children with PRDs and their parents may be at increased risk for psychological problems, especially during the active disease phase, highlighting the importance of a multidisciplinary approach.

Role of ductus venosus agenesis in right ventricle development.

Ductus venosus agenesis (DVA) results from portal-umbilical and hepatic-systemic venous system connection failure. Despite a large series of DVA was reported, an accurate description of single fetus cardiac trend with hemodynamic consequences is missing. We describe two fetuses with DVA early detection, comparing right ventricle (RV) development in extrahepatic and intrahepatic drainages. In extrahepatic drainage, the RV was larger and slightly hypertrophic. In intrahepatic drainage, the RV showed reduced dimensions. Ventricle dimension differences decreased and became balanced in perinatal period. Detection of non-balanced ventricles in early second trimester should lead to sonographic follow-up. If DVA is hypothesized, it is important to identify other subdiaphragmatic connections that could alter cardiac preload and ventricle development.

Chromosomal Microarray Analysis in Fetuses Detected with Isolated Cardiovascular Malformation: A Multicenter Study, Systematic Review of the Literature and Meta-Analysis.

Cardiovascular malformations (CVM) represent the most common structural anomalies, occurring in 0.7% of live births. The CVM prenatal suspicion should prompt an accurate investigation with fetal echocardiography and the assessment through genetic counseling and testing. In particular, chromosomal microarray analysis (CMA) allows the identification of copy number variations. We performed a systematic review and meta-analysis of the literature, studying the incremental diagnostic yield of CMA in fetal isolated CVM, scoring yields for each category of heart disease, with the aim of guiding genetic counseling and prenatal management. At the same time, we report 59 fetuses with isolated CVM with normal karyotype who underwent CMA. The incremental CMA diagnostic yield in fetuses with isolated CVM was 5.79% (CI 5.54-6.04), with conotruncal malformations showing the higher detection rate (15.93%). The yields for ventricular septal defects and aberrant right subclavian artery were the lowest (2.64% and 0.66%). Other CVM ranged from 4.42% to 6.67%. In the retrospective cohort, the diagnostic yield was consistent with literature data, with an overall CMA diagnostic yield of 3.38%. CMA in the prenatal setting was confirmed as a valuable tool for investigating the causes of fetal cardiovascular malformations.