Cardiac function evaluation in children with spinal muscular atrophy: A case-control study.

BACKGROUND: Spinal muscular atrophy (SMA) is an autosomal recessive disorder characterized by degeneration of lower motor neurons, resulting in progressive muscle weakness and atrophy. However, little is known regarding the cardiac function of children with SMA. METHODS: We recruited SMA patients younger than 18 years of age from January 1, 2022, to April 1, 2022, in the First Affiliated Hospital of Sun Yat-sen University. All patients underwent a comprehensive cardiac evaluation before treatment, including history taking, physical examination, blood tests of cardiac biomarkers, assessment of echocardiography and electrocardiogram. Age/gender-matched healthy volunteers were recruited as controls. RESULTS: A total of 36 SMA patients (26 with SMA type 2 and 10 with SMA type 3) and 40 controls were enrolled in the study. No patient was clinically diagnosed with heart failure. Blood tests showed elevated values of creatine kinase isoenzyme M and isoenzyme B (CK-MB) mass and high-sensitivity cardiac troponin T (hs-cTnT) in spinal muscular atrophy (SMA) patients. Regarding echocardiographic parameters, SMA children were detected with lower global left and right ventricular longitudinal strain, abnormal diastolic filling velocities of trans-mitral and trans-tricuspid flow. The results revealed no clinical heart dysfunction in SMA patients, but subclinical ventricular dysfunction was seen in SMA children including the diastolic function and myocardial performance. Some patients presented with elevated heart rate and abnormal echogenicity of aortic valve or wall. Among these SMA patients, seven patients (19.4%) had scoliosis. The Cobb's angles showed a significant negative correlation with LVEDd/BSA, but no correlation with other parameters, suggesting that mild scoliosis did not lead to significant cardiac dysfunction. CONCLUSIONS: Our findings warrant increased attention to the cardiac status and highlight the need to investigate cardiac interventions in SMA children.

Duchenne Muscular Dystrophy With Low Acidic α-Glucosidase Activity: Two Case Reports and Literature Review.

Background: Pompe disease is usually considered in children with elevated creatine kinase (CK) levels and decreased acidic α-glucosidase (GAA) enzyme activity. However, there are exceptions, such as GAA pseudo deficiency alleles, which result in lower GAA enzyme activity but do not cause Pompe disease. Here, we report two cases presenting with high CK levels and low GAA activity who were ultimately diagnosed with Duchenne muscular dystrophy (DMD). Case Presentation: Case 1 patient was a 2-month-old boy who presented with an extremely high serum CK level (5,480∼11,880 U/L) and low GAA activity (2.72 nmol/1 h/mg). The whole-exome sequencing did not find the pathogenic GAA gene mutation, however, there was a DMD gene hemizygous variation (c. 7657C > T, p. Arg2553Ter) inherited from his mother, which was verified by the first-generation sequencing. Further genetic analysis of GAA identified two homozygous pseudo deficiency alleles (c.1726G > A, p. Gly576Ser and c.2065G > A, p. Glu689Lys), which were believed to induce the patient's low GAA activity. Therefore, the boy was diagnosed with DMD, although he had extremely low GAA activity. Case 2 patient was also a 2-month-old boy presenting with a significant increase in CK level (12,408∼24,828 U/L). His blood GAA activity (colorimetric method) was 9.02 nmol/1 h/mg. Similarly, his whole-exome sequencing did not find the pathogenic mutation of the GAA gene, but a DMD gene hemizygous variation (c.5571del, p. Lys1857AsnfsTer8), hence he was diagnosed with DMD as well. Regarding GAA activity, the case 2 patient was not as low as the case 1 patient, mainly because his two GAA pseudo deficiency alleles were heterozygous. Conclusion: Pompe disease is usually screened in infants with high CK levels. We should be aware that pseudo deficiency alleles can cause low GAA activities but not Pompe disease. Genetic tests would be helpful to distinguish cases with GAA pseudo deficiency alleles from patients with some muscular disorder diseases such as DMD.

Stent implantation in severe aortic coarctation in a pediatric patient with Turner syndrome: Case report and literature review.

Background: Turner syndrome is a rare systemic disease and a significant proportion of these patients experience aortic coarctation. Selection of optimal therapy for aortic coarctation in patients with Turner syndrome is difficult due to the pathologic change of the systemic vessel. Case presentation: We report one successful case of covered stent implantation for the treatment of severe native coarctation of the aorta in a 15-year-old patient with Turner syndrome weighing 36 kg. A covered stent was implanted in this patient. After the stent implantation, the peak systolic pressure gradient immediately decreased from 48 mmHg to 14 mmHg. The aortic diameter at the coarctation site increased from 3 mm to 10 mm after stenting. A femoral arterial complication occurred in this case, and we stabilized the situation finally. Results: During a follow-up of 3 years, no restenosis of aortic coarctation was observed and the patient no longer experienced hypertension. The dissection of the right femoral artery remained stable. Conclusion: A covered stent implantation for severe aortic coarctation in patients with Turner syndrome could be safe and effective. However, caution should be taken when using the technique to prevent complications.

Haploinsufficiency of A20 in a Chinese child caused by loss-of-function mutations in TNFAIP3: A case report and review of the literature.

Case Presentation: A 3-year-and-6-month-old child was reported to have recurrent high fever with generalized lymph node enlargement and significant elevation of inflammatory markers such as C-reactive protein and procalcitonin in tests. Later, whole exome sequencing determined that the child's disease was haploinsufficiency of A20 (HA20). Results: After immunosuppressive therapy, the child's symptoms improved significantly, and the inflammatory markers dropped to the normal range. Conclusion: Because of the characteristics of HA20, this disease is often underdiagnosed and misdiagnosed in clinical practice. By reporting this case of HA20 in a child, we hope to increase the awareness of this disease in the clinic.

Case Report: Talaromyces marneffei Infection in a Chinese Child With a Complex Heterozygous CARD9 Mutation.

Talaromyces marneffei (TM) infection is rarely seen in clinical practice, and its pathogenesis may be related to deficiency in antifungal immune function. Human caspase recruitment domain-containing protein 9 (CARD9) is a key molecule in fungal immune surveillance. There have been no previous case reports of TM infection in individuals with CARD9 gene mutations. Herein, we report the case of a 7-month-old Chinese boy who was admitted to our hospital with recurring cough and fever with a papular rash. A blood culture produced TM growth, which was confirmed by metagenomic next-generation sequencing. One of the patient's sisters had died of TM septicaemia at 9 months of age. Whole exome sequencing revealed that the patient had a complex heterozygous CARD9 gene mutation with a c.1118G>C p.R373P variation in exon 8 and a c.610C>T p.R204C variation in exon 4. Based on the culture results, voriconazole antifungal therapy was administered. On the third day of antifungal administration, his temperature dropped to within normal range, the rash gradually subsided, and the enlargement of his lymph nodes, liver, and spleen improved. Two months after discharge, he returned to the hospital for a follow-up examination. His general condition was good, and no specific abnormalities were detected. Oral voriconazole treatment was continued. Unexplained TM infection in HIV-negative individuals warrants investigation for immune deficiencies.

Sitosterolemia With Atherosclerosis in a Child: A Case Report.

Introduction: Sitosterolemia is a rare condition in children and is often misdiagnosed as familial hypercholesterolemia. Serious complications can result if not treated promptly and effectively. When pediatric patients are diagnosed with sitosterolemia, vascular, and cardiac studies are important to evaluate for the presence of atherosclerosis. Few cases of severe atherosclerotic heart disease in children with sitosterolemia have been reported, making this case worthy of presentation. Case Presentation: Here, we report a case of sitosterolemia in an 8-year-old child. The patient presented with severe hypercholesterolemia and xanthoma. He was diagnosed two and a half years prior with familial hypercholesterolemia because his father had elevated cholesterol levels. After conventional treatment, the patient was dissatisfied with lipid level control and visited our hospital for further management. Genetic tests of the patient and parents found mutations in intron 7 (NM 022436.2, c.904+1G>A) and intron 9 (NM 022436.2, C. 1324+1de1G) of ABCG5. The 7 intron mutation was from his mother, and the 9 intron mutation was from his father. The patient was diagnosed with sitosterolemia. Results: The child was treated with ezetimibe, a low plant sterol diet, and clopidogrel anticoagulant therapy. After 3 months of treatment, the blood lipid level was significantly lower. Conclusion: Genetic testing should be completed as soon as possible to avoid misdiagnosis in children with abnormally elevated hypercholesterolemia who have a family history of elevated cholesterol. In addition, clinicians should rule out great arterial lesions and be vigilant in evaluating patients for systemic arterial disease and atherosclerosis.

Treatment Option for Abernethy Malformation-Two Cases Report and Review of the Literature.

Background: Abernethy malformation is a rare vascular anomaly of the portal venous system, which is also known as congenital portosystemic shunts (CPSS). The clinical manifestations of this anomaly can be serious, including hepatopulmonary syndrome(HPS), which can lead to significant hypoxemia and cyanosis. Case Presentation: This study reports two cases of patients with Abernethy Malformation. Case 1 was a 6-year-old boy whose blood oxygen saturation was 78%. Case 2 was a 6-year-old girl who had a history of open heart surgery and residual cardiac left to right shunt, whose blood oxygen saturation was 83%. These two children had unexplained cyanosis and were diagnosed with pulmonary arteriovenous fistula by contrast echocardiography with agitated saline. A selective retrograde catheter angiography confirmed the presence of a portosystemic shunt. Case 1 was a type I Abernethy malformation and did not receive any specific treatment and could only wait for liver transplantation. Case 2 was with type II Abernethy and underwent transcatheter closure of the CPSS. A 20mm-diameter, 14mm-long Vascular Plug (SHSMA Inc, Shanghai, China) was used to occlude the shunt. Results: In case 1, the boy developed deteriorating cyanosis and dyspnea on exertion. In case 2, the exercise tolerance of the patient improved after shunt closure. During a follow-up of 3 years, her blood oxygen saturation increased from 83 to 98%. Conclusion: The results indicate that children with unexplained cyanosis require special attention since these patients may have Abernethy malformation, and part of them could be treated by transcatheter occlusion with a good outcome. The key to treatment is how it is diagnosed and carefully assessed.

Beta Blocker Therapy for Congenital Hepatic Arteriovenous Fistula in Two Neonates.

Introduction: Hepatic arteriovenous fistula (HAVF) is an abnormal communication between the hepatic arteries and hepatic veins. This condition is treated mainly using interventional closure and surgery. However, these procedures are associated with many postoperative complications and high mortality. Propranolol and other beta blockers have been used widely and effectively to treat infantile hemangiomas. However, no reports describe the use of these drugs to treat congenital HAVF. Case Description:Here, we present two cases in which beta blocker therapy was used to treat congenital HAVF in neonates. In both cases, antenatal examinations revealed cardiac enlargement and hepatic space-occupying lesions. After birth, both patients rapidly presented with respiratory distress, cyanosis, and heart failure. Echocardiography suggested enlargement of the right heart, widening of the pulmonary artery, and severe pulmonary arterial hypertension, and hepatic examinations revealed HAVF. Results:After admission, the patients were treated with dopamine, milinone, and furosemide for heart failure. However, their conditions worsened, as indicated by nod-like breathing and cyanosis. Endotracheal intubation and ventilator-assisted breathing and a small dose of oral propranolol (1 mg/kg/d) were initiated. The patients' conditions improved, as indicated by decreases in levels of the N-terminal pro-hormone BNP, and the ventilators were removed. The propranolol dose was increased gradually to 2 mg/kg/d. After 2 weeks of propranolol treatment, the neonate in case 2 developed bronchospasm, which improved after propranolol treatment ended and metoprolol treatment was initiated. Liver imaging performed 8-9 months after beta blocker therapy suggested the disappearance of the arteriovenous fistulae in case 2, and close to disappearing of the arteriovenous fistulae in case 1. Conclusion:Propranolol and metoprolol can effectively treat HAVF in infants, an observation consistent with that found in earlier studies that have shown beta blockers are a valid medical treatment option for infantile hemangioma. However, future studies should explore the underlying potential mechanism.

Amiodarone-Related Pure Red Cell Aplastic Anemia and Hypothyroidism in a Child With Total Anomalous Pulmonary Venous Connection.

Introduction: Amiodarone is an effective anti-arrhythmic drug, but there are many clinical side effects that limit its application. There are no case reports of amiodarone-related pure red cell aplastic anemia (PRCA). Case Presentation: Here, we present a case of amiodarone-related PRCA and hypothyroidism in a 7-month-old boy. The patient had a total anomalous pulmonary venous connection (the cardiac type) and had undergone cardiac surgery at the age of 2 months. Eleven days after the operation, atrial tachycardia was observed. Amiodarone was administered orally (15 mg/kg.d), following which the arrhythmia was under control. Subsequently, the patient was prescribed amiodarone (5 mg/kg.d) and discharged. Regular medical consultations were not conducted as required. At 7 months of age (5 months after the operation), the patient returned to the hospital for re-examination. The electrocardiogram showed intermittent sinus bradycardia, occasional junctional escape beats, hemoglobin 7.9 g/DL, and thyroid function-TSH 9.660 uIU/mL. Results: Amiodarone was discontinued. Thyroxine was administered orally. Subsequently, the heart rate improved and TSH returned to normal levels. Nutritional therapy was recommended based on a diagnosis of nutrition-related anemia. A re-visit at 9 months of age showed that the weight was 6 kg, but the routine blood test indicated that hemoglobin was 5.9 g/DL with positive cell anemia and low reticulocyte count. Bone marrow cytology examination suggested PRCA. The hemoglobin level was gradually restored after treatment with prednisone. Conclusion: The use of amiodarone in small infants and young children and its side effects should be carefully monitored. The potential mechanism of amiodarone-related PRCA needs further study.

Chronic Active Epstein-Barr Virus Infection With Systemic Vasculitis and Pulmonary Arterial Hypertension in a Child.

Introduction: A chronic active Epstein-Barr virus (EBV) infection (CAEBV), which is characterized by persistent "infectious mononucleosis-like" symptoms, can lead to cardiovascular complications, including coronary artery aneurysms. No published studies have reported an occurrence of chronic EB virus infection in conjunction with systemic vasculitis and pulmonary hypertension. Case Presentation: Herein, we present a case of a 9-year-old boy with CAEBV, associated with pulmonary arterial hypertension (PAH) and systemic vasculitis. Recurrent skin ulcers were a major early clinical manifestation in this case. The histopathological examination of a dermal biopsy sample from the lesions revealed vasculitis, and the in-situ hybridization test was positive for EBV-encoded small RNA. Results: The patient was administered immunosuppressants (prednisolone and cyclophosphamide) and targeted drugs (sildenafil and bosentan) to control the pulmonary pressure. This combination therapy decreased the systolic pulmonary arterial pressure to 40 mm Hg (on echocardiography), and the N-terminal pro b-type natriuretic peptide level also reduced to 62.3 pg/ml. After discontinuation of prednisone, the child developed shortness of breath, edema, and oliguria. He was again started on prednisone, with an addition of thalidomide. Sildenafil was replaced by riociguat, due to the side effect of penile erection. The patient is being followed up every 2 months at the clinic. The most recent follow-up visit was 2 weeks before this report was written, during which, the child was observed to have no rash, shortness of breath, edema, and other symptoms. Written informed consent was obtained from the parents for the publication of this case report. Conclusion: A CAEBV should be considered among the differential diagnoses while managing a pediatric patient with secondary PAH and systemic vasculitis. However, elucidation of its potential pathophysiological mechanisms requires further study.

Left Ventricular Mechanics Assessed by 2-dimensional Speckle Tracking Echocardiography in Children and Adolescents With Idiopathic Scoliosis.

STUDY DESIGN: A retrospective review of data collected prospectively. OBJECTIVE: The study aimed to assess the possible effects of idiopathic scoliosis on left ventricular (LV) myocardial performance in children and adolescent patients. SUMMARY OF BACKGROUND DATA: Spine anomaly may impair cardiorespiratory function. It has been confirmed that respiratory function decreased in patients with scoliosis. However, limited study of the effect of scoliosis on heart function has been published, and no assessment of myocardial deformation of these patients has been reported to our knowledge. METHODS: Forty-one patients with a median age of 16 years and a median Cobb's angle of 75 degrees were studied. LV myocardial deformation was evaluated using 2-dimensional speckle-tracking echocardiography. The results were compared with those of 33 controls. The correlations between Cobb's angle and echocardiographic parameters in patients were also explored. RESULTS: Compared with controls, patients had significantly lower global LV longitudinal systolic strain in all 3 views (4 chamber, 2 chamber, and 3 chamber views), lower global radial and circumferential strains in mitral valve (MV) level and papillary muscle (PM) level; reduced LV longitudinal early diastolic strain rate (SRe) in all 3 longitudinal views and reduced radial SRe in MV level and reduced circumferential SRe in apical (AP) level; decreased LV longitudinal late diastolic strain rate in 4-chamber view and decreased radial ones in all 3 short-axis levels. Among patients, Cobb's angle correlated negatively with LV global radial strain of MV level (r=-0.37, P=0.02), global circumferential strain of MV level (r=-0.35, P=0.03), and global circumferential strain of PM level (r=-0.49, P=0.001), whereas positively with LV longitudinal SRa of 4-chamber view (r=0.46, P=0.003), longitudinal SRa of 2-chamber view (r=0.49, P=0.001), and circumferential SRa of AP level (r=0.35, P=0.02). CONCLUSIONS: LV mechanics are impaired in patients with idiopathic scoliosis, which correlate with the severity of scoliosis. Our findings suggest the need and provide a mechanical basis for further studies in these patients.

Pentoxifylline Prevents Driamycin-Induced Myocardial Fibrosis and Apoptosis in Rats.

Adriamycin (ADR) is a potent antineoplastic agent, but long-term treatment is limited by its cumulative, life-threatening cardiomyopathy. Recently, a few reports have shown that pentoxifylline (PTX) might produce cardioprotection in cardiac dysfunction. Here, we investigated the protective effects of PTX on ADR-induced cardiomyopathy in rats. Male rats were randomly assigned either to saline, ADR (adriamycin, 5 mg/kg/week), or A (adriamycin, 5 mg/kg/week) + PTX (pentoxifylline, 50 mg/kg/day) groups. After 3 weeks, these animals were sacrificed and the heart tissue was harvested for histological analysis and assessment of hepatocyte growth factor (HGF) and caspase-3 expression. Histopathological findings showed that PTX can alleviate myocardial damage caused by ADR. Cardiac fibrosis was significantly suppressed in the A+PTX group compared to that in the ADR group. The HGF gene expression was decreased significantly in the ADR group compared with the control group, but was increased in the A+PTX group. Caspase-3 was up-regulated in the ADR group, and down-regulated in the A+PTX group. These results show that treatment with PTX exerts a protective effect against ADR-induced myocardial fibrosis via regulation of HGF and caspase-3 gene expression. PTX may thus represent a useful new clinical tool for the treatment of ADR-induced cardiomyopathy.

Ventricular and atrial mechanics and their interaction in patients with congenital scoliosis without clinical heart failure.

OBJECTIVES: This study sought to evaluate left ventricular, right ventricular, and left atrial mechanics and their interactions in patients with congenital scoliosis without clinical heart failure. METHODS: A total of 23 patients with a median age of 14 years and a median Cobb's angle of 61° were studied. Ventricular and atrial myocardial deformation was measured using speckle tracking echocardiography. The results of the patients were compared with 22 controls. RESULTS: Compared with controls, the patients had a significantly greater annular a velocity (p=0.04) and lower e/a ratio (p=0.03); the left ventricular deformation significantly decreased in radial global (p=0.04) and segmental systolic strain and early diastolic strain rate (p=0.03); the left atrial deformation showed a significantly lower positive strain (p=0.02), greater negative strain (p=0.01), and active contractile strain rate (p=0.01). For the patients, the Cobb's angle was negatively correlated with the left ventricular global radial systolic strain (r=-0.65, p=0.001), left atrial positive strain (r=-0.68, p<0.001), and the left atrial negative strain was positively correlated with the left ventricular circumferential late diastolic strain rate (r=0.46, p=0.01). The left atrial conduit strain rate was positively correlated with the left ventricular circumferential early diastolic strain rate (r=0.42, p=0.03). The left atrial active contractile strain rate was positively correlated with the left ventricular longitudinal late diastolic strain rate (r=-0.4, p=0.03). CONCLUSIONS: Impaired left ventricular and altered left atrial mechanics occur relatively early in patients with congenital scoliosis, and are correlated with the severity of their scoliosis. Our findings provide evidence of preclinical heart dysfunction in patients with this disorder.

H2S inhibition of chemical hypoxia-induced proliferation of HPASMCs is mediated by the upregulation of COX-2/PGI2.

The hypoxia-induced proliferation of pulmonary artery smooth muscle cells (PASMCs) is the main cause of pulmonary arterial hypertension (PAH), in which oxidative stress, cyclooxygenase (COX)-2 and hydrogen sulfide (H(2)S) all play an important role. In the present study, we aimed to examine the effects of H(2)S on the hypoxia-induced proliferation of human PASMCs (HPASMCs) and to elucidate the underlying mechanisms. The HPASMCs were treated with cobalt chloride (CoCl(2)), a hypoxia-mimicking agent, to establish a cellular model of hypoxic PAH. Prior to treatment with CoCl(2), the cells were pre-conditioned with sodium hydrosulfide (NaHS), a donor of H(2)S. Cell proliferation, reactive oxygen species (ROS) production, COX-2 expression, prostacyclin (also known as prostaglandin I2 or PGI(2)) secretion and H(2)S levels were detected in the cells. The exposure of the HPASMCs to CoCl(2) markedly increased cell proliferation, accompanied by a decrease in COX-2 expression, PGI(2) secretion and H(2)S levels; however, the levels of ROS were not altered. Although the exogenous ROS donor, H(2)O(2), triggered similar degrees of proliferation to CoCl(2), the ROS scavenger, N-acetyl-L-cysteine (NAC), markedly abolished the H(2)O(2)­induced cell proliferation, as opposed to the CoCl(2)-induced proliferation. The CoCl(2)-induced proliferation of HPASMCs was suppressed by exogenously applied PGI(2). The addition of H(2)S (NaHS) attenuated the CoCl(2)-induced cell proliferation through the increase in the intercellular content of H(2)S. Importantly, the exposure of the cells to H(2)S suppressed the CoCl(2)-induced downregulation in COX-2 expression and PGI(2) secretion from the HPASMCs. In conclusion, the results from the current study suggest that H(2)S enhances hypoxia-induced cell proliferation through the upregulation of COX-2/PGI(2), as opposed to ROS.

Right ventricular function impaired in children and adolescents with severe idiopathic scoliosis.

BACKGROUND: Although it is speculated that scoliosis may induce cardiac dysfunction, there is no report about evaluation of cardiac function, especially right cardiac function in patients with scoliosis. Therefore, we evaluated right ventricular function in idiopathic scoliotic patients with mild to severe curves and compared them with healthy children and adolescents matched in age, then explored relationship between scoliosis and right ventricular function. METHODS: Thirty-seven patients diagnosed with idiopathic scoliosis with a mean age of 16y/o (range, 8-25y/o) and an average spine curve of 77.5°Cobb (range, 30-157°) were studied by echocardiography. TAD was obtained using M-mode echocardiography. Similar examination was performed in a control group of 17 healthy individuals in matched-age. According to the different curve degree, all patients were divided into 3 groups (mild, moderate and severe). Comparison was done among the groups and the relationship between TAD and spine curve of Cobb was analyzed. RESULTS: Patients with severe scoliosis showed depressed TAD. There was good correlation between TAD and spine curve of Cobb. CONCLUSIONS: Patients with severe scoliosis showed a significant lower right ventricular systolic function.