Hyperinflammatory syndrome in a paediatric patient with a recent diagnosis of HIV/AIDS infection: hemophagocytic lymphohistiocytosis or immune reconstitution syndrome?

INTRODUCTION: Haemophagocytic lymphohistiocytosis is a rare and life-threatening condition caused by uncontrolled immune activation leading to excessive inflammation and tissue destruction. It could either be due to a primary genetic defect or be triggered by secondary causes such as infections, autoimmune diseases, rheumatological diseases or post-transplant immunosuppression. We here report the case of a 4-year-old child with a recent AIDS diagnosis who developed a severe systemic inflammation. CASE REPORT: We here report the case of a 4-year-old child with a recent AIDS diagnosis who was admitted to the ER with acute respiratory failure due to Pneumocystis jiroveci infection and Aspergillosis; the following microbiological assessment also showed a CMV, HSV, EBV and HHV-7 coinfection. On the 51st day after she'd started antiretroviral therapy, 39th after she'd followed a course of Bactrim and Caspofungin for PJI and Ambisome for pulmonary Aspergillosis, she started presenting fever, unresponsive to broad-spectrum antibiotic therapy. She also presented worsening of her clinical conditions, with evidence at the laboratory assessments of progressive raise in inflammatory indexes, coagulopathy, trilinear cytopenia and hyperferritinemia. To perform the differential diagnosis between IRIS and HLH, HLA-DR on T cells was studied, turning out negative for IRIS. Therefore, in the suspicion of HLH, a bone marrow aspirate and biopsy were performed with evidence of trilinear cytopenia, prevalence of T-cells and macrophages with signs of phagocytosis. She was started on high-dose steroids and Anakinra for a total of 29 days, resulting in prompt apyrexia and progressive improvement of her clinical conditions and laboratory results. CONCLUSION: To the best of our knowledge there is poor literature available about the differential diagnosis of HLH and IRIS, therefore medical management in the concurrence of these two conditions needs to be further investigated, especially in a setting where immunological testing is not quickly available. The clinical differences between these pathologies are blurred and the bone marrow biopsy within marker for IRIS helped us to distinguish these two entities.

The heart in RASopathies.

The cardiovascular phenotype associated with RASopathies has expanded far beyond the original descriptions of pulmonary valve stenosis by Dr Jaqueline Noonan in 1968 and hypertrophic cardiomyopathy by Hirsch et al. in 1975. Because of the common underlying RAS/MAPK pathway dysregulation, RASopathy syndromes usually present with a typical spectrum of overlapping cardiovascular anomalies, although less common cardiac defects can occur. The identification of the causative genetic variants has enabled the recognition of specific correlations between genotype and cardiac phenotype. Characterization and understanding of genotype-phenotype associations is not only important for counseling a family of an infant with a new diagnosis of a RASopathy condition but is also critical for their clinical prognosis with respect to cardiac disease, neurodevelopment and other organ system involvement over the lifetime of the patient. This review will focus on the cardiac manifestations of the most common RASopathy syndromes, the relationship between cardiac defects and causal genetic variation, the contribution of cardiovascular abnormalities to morbidity and mortality and the most relevant follow-up issues for patients affected by RAS/MAPK pathway diseases, with respect to cardiac clinical outcomes and management, in children and in the adult population.

Persistent myocardial atrophy despite LV reverse remodeling in Duchenne cardiomyopathy treated by LVAD.

DCM is the leading cause of death in Duchenne patients. LVADs are considered as therapeutic options as DT in advanced HF. The aim of our study was to evaluate LV remodeling of Duchenne after LVADs and chronic therapy. Demographic and echocardiographic data of 8 Duchenne patients implanted with LVADs were reviewed and analyzed. All measures were collected before LVAD implantation, after 1 month and 1 year. All patients were affected by end-stage DCM, and mean age at implantation was 16.9 ± 2.9 years. Patients were treated with maximal medical therapy. One-year post-implantation HR decreased from a mean of 110 ± 19 bpm to 82 ± 2 bpm (P = .002), and a significant decrease in LV volumes and diameters LVEDD P = .03, LVESD P = .02, EDV P = .01, and ESV P = .02) was noticed together with a significant increase in EF (P = .0036). However, RWT did not change over time, showing an eccentric remodeling pattern pre- and post-LVADs. Our data showed that cardiac atrophy is persistent in Duchenne cardiomyopathy despite the improvement of LV function secondary to a significant ventricular unloading due to LVADs coupled with chronic therapy.

Delayed appearance of 3-methylglutaconic aciduria in neonates with early onset metabolic cardiomyopathies: A potential pitfall for the diagnosis.

Infantile onset cardiomyopathies are highly heterogeneous with several phenocopies compared with adult cardiomyopathies. Multidisciplinary management is essential in determining the underlying etiology in children's cardiomyopathy. Elevated urinary excretion of 3-methylglutaconic acid (3-MGA) is a useful tool in identifying the etiology in some metabolic cardiomyopathy. Here, we report the delayed appearance of 3-MGA-uria, between 6 and 18 months in three patients (out of 100 childhood onset cardiomyopathy) with neonatal onset cardiomyopathy, secondary to TMEM70 mutations and TAZ mutations (Barth syndrome), in whom extensive metabolic investigations, performed in the first weeks of life, did not display 3-MGA-uria. Serial retrospective evaluations showed full characteristic features of TMEM70 and TAZ mutations (Barth syndrome) in these three patients, including a clearly abnormal monolysocardiolipin/cardiolipin ratio in the two Barth syndrome patients. Serially repeated metabolic investigations finally discovered the 3-MGA-uria biomarker in all three patients between the age of 6 and 18 months. Our observation provides novel insights into the temporal appearance of 3-MGA-uria in TMEM70 and TAZ mutations (Barth syndrome) and focus the importance of multidisciplinary management and careful evaluation of family history and red flag signs for phenocopies in infantile onset cardiomyopathies.

Differences in morbidity and mortality in Down syndrome are related to the type of congenital heart defect.

Morbidity and mortality in Down syndrome (DS) are mainly related to congenital heart defects (CHDs). While CHDs with high prevalence in DS (typical CHDs), such as endocardial cushion defects, have been extensively described, little is known about the impact of less common CHDs (atypical CHDs), such as aortic coarctation and univentricular hearts. In our single-center study, we analyzed, in observational, retrospective manner, data regarding cardiac features, surgical management, and outcomes of a cohort of DS patients. Literature review was performed to investigate previously reported studies on atypical CHDs in DS. Patients with CHDs were subclassified as having typical or atypical CHDs. Statistical analysis was performed for comparison between the groups. The study population encompassed 859 DS patients, 72.2% with CHDs, of which 4.7% were atypical. Statistical analysis showed a significant excess in multiple surgeries, all-cause mortality and cardiac mortality in patients with atypical CHDs (p = .0067, p = .0038, p = .0001, respectively). According to the Kaplan-Meier method, survival at 10 and 40 years was significantly higher in typical CHDs (99 and 98% vs. 91 and 84%, log rank <0.05). Among atypical CHDs, it seems that particularly multiple complex defects in univentricular physiology associate with a worse outcome. This may be due to the surgical difficulty in managing univentricular hearts with multiple defects concurring to the clinical picture or to the severity of associated defects themselves. Further studies need to address this specific issue, also considering the higher pulmonary pressures, infective complications, and potential comorbidities in DS patients.

SOS1 mutations in Noonan syndrome: Cardiomyopathies and not only congenital heart defects! Report of six patients including two novel variants and literature review.

Noonan syndrome (NS) is caused by mutations in more than 10 genes, mainly PTPN11, SOS1, RAF1, and RIT1. Congenital heart defects and cardiomyopathy (CMP) are associated with significant morbidity and mortality in NS. Although hypertrophic CMP has "classically" been reported in association to RAF1, RIT1, and PTPN11 variants, SOS1 appears to be poorly related to CMP. Patients with NS attending our Center from January 2013 to June 2018 were eligible for inclusion if they carried SOS1 variants and presented with-or developed-CMP. Literature review describing the co-existence of SOS1 mutation and CMP was also performed. We identified six patients with SOS1 variants and CMP (male to female ratio 2:1) including two novel variants. CMP spectrum encompassed: (a) dilated CMP, (b) nonobstructive hypertrophic CMPs, and (c) obstructive hypertrophic CMPs. Survival is 100%. Literature review included 16 SOS1 mutated in CMP. CMP, mainly hypertrophic, has been often reported in association to RAF1, RIT1, and PTPN11 variants. Differently from previous reports, due to the frequent association of SOS1 variants and CMP in our single center experience, we suggest potential underestimated proportion of SOS1 in pediatric CMPs.

First evidence of maternally inherited mosaicism in TGFBR1 and subtle primary myocardial changes in Loeys-Dietz syndrome: a case report.

BACKGROUND: Loeys-Dietz syndrome (LDS) is a rare multisystemic disorder characterized by vascular and skeletal abnormalities, with considerable intra- and interfamilial variability. CASE PRESENTATION: We report the case of an 8-year-old male with clinical features of two distinct genetic disorders, namely LDS, manifesting in the first months by progressive aortic root dilatation, arterial tortuosity, bifid uvula, and inguinal hernias and oculocutaneous albinism (OCA) manifesting by white hair and skin that does not tan, nystagmus, reduced iris pigment with iris translucency, and reduced retinal pigment). We identified previously reported, homozygous mutations of TYR, c.1A > G (p.Met1Val) and heterozygous, missense mutation of TGFBR1, c.1460G > A (p.Arg487Gln). Family history revealed that his mother underwent multiple surgical repairs for recurrent hemorrhage originating from the buccal artery. Molecular studies confirmed a maternally inherited low grade TGFBR1 mutation somatic mosaicism (18% in peripheral blood leukocytes, 18% in buccal cells and 10% in hair root cells). Maternal cardiac investigations revealed peculiar cardiovascular features: mild tortuosity at the aortic arch, dilatation of the proximal abdominal aorta, multiple deep left ventricular myocardial crypts, and dysplastic mitral valve. TGFBR2 germline mosaicism has been described in three fathers of children carrying TGFBR2 mutations but, to the best of our knowledge, no case of maternally inherited TGFBR1 mutation mosaicism has been reported so far. CONCLUSIONS: This case report suggests that individuals with somatic mosaicism might be at risk for mild and unusual forms of LDS but germline mosaicism can lead to full blown picture of the disease in offspring.

A New 2D Echocardiographic Approach to Evaluate the Membrane and Valve Movement of the Berlin Heart EXCOR VAD Chamber in Pediatric VAD Patients.

The use of Berlin Heart EXCOR VAD (BH) is a validated therapy to bridge pediatric patients to heart transplant. Serial echocardiographic (ECHO) assessment of VAD patients is necessary to support patients' management. This work aims at developing an innovative strategy to evaluate the BH device functioning by ECHO and its interaction with the native heart in a pediatric population. ECHO evaluation of BH membrane movement, and inflow and outflow valves was performed in 2D, 2D-color Doppler, M-mode, and M-mode color Doppler to assess the functioning of the device by direct positioning of the ECHO probe on the BH cannulas and membranes. Forty Berlin Heart EXCOR VAD were analyzed in 18 patients. Seven BH were placed as RVAD and 33 as LVAD. Results evidenced that 14 (21) inflow (outflow) valves presented a mild regurgitation, while 5 inflow (3 outflow) valves presented a moderate regurgitation. In three cases, we observed severe valve regurgitation with back flow in the left ventricle/right atrium. In both cases, the BH chambers were substituted, but we observed that in one case the regurgitation was due to cannulas compression, while in the other case it was due to valve malfunctioning. The M-mode and the ECHO of the membranes and valves permitted to appreciate the beat phenomenon to assess if the native heart and the BH are working in opposite or in the same phase. The membrane ECHO permits evaluation of minimal changes in membrane movement to assure the completely empty-completely fully work modality. Systematic ECHO assessment of BH chamber might support the BH programming and the detection of anomalous VAD-heart interaction.

Clinical Presentation and Natural History of Hypertrophic Cardiomyopathy in RASopathies.

RASopathies are a heterogeneous group of genetic syndromes characterized by mutations in genes that regulate cellular processes, including proliferation, differentiation, survival, migration, and metabolism. Excluding congenital heart defects, hypertrophic cardiomyopathy is the most frequent cardiovascular defect in patients affected by RASopathies. A worse outcome (in terms of surgical risk and/or mortality) has been described in a specific subset of Rasopathy patients with early onset, severe hypertrophic cardiomyopathy presenting with heart failure. New short-term therapy with a mammalian target of rapamycin inhibitor has recently been used to prevent heart failure in these patients with a severe form of hypertrophic cardiomyopathy.

Consensus Document of the Italian Association of Hospital Cardiologists (ANMCO), Italian Society of Pediatric Cardiology (SICP), and Italian Society of Gynaecologists and Obstetrics (SIGO): pregnancy and congenital heart diseases.

The success of cardiac surgery over the past 50 years has increased numbers and median age of survivors with congenital heart disease (CHD). Adults now represent two-thirds of patients with CHD; in the USA alone the number is estimated to exceed 1 million. In this population, many affected women reach reproductive age and wish to have children. While in many CHD patients pregnancy can be accomplished successfully, some special situations with complex anatomy, iatrogenic or residual pathology are associated with an increased risk of severe maternal and fetal complications. Pre-conception counselling allows women to come to truly informed choices. Risk stratification tools can also help high-risk women to eventually renounce to pregnancy and to adopt safe contraception options. Once pregnant, women identified as intermediate or high risk should receive multidisciplinary care involving a cardiologist, an obstetrician and an anesthesiologist with specific expertise in managing this peculiar medical challenge. This document is intended to provide cardiologists working in hospitals where an Obstetrics and Gynecology Department is available with a streamlined and practical tool, useful for them to select the best management strategies to deal with a woman affected by CHD who desires to plan pregnancy or is already pregnant.

The use of a numerical model to simulate the cavo-pulmonary assistance in Fontan circulation: a preliminary verification.

The lack of an established experience on the use of VAD for the cavo-pulmonary assistance leads to the need of dedicated VADs development and animal experiments. A dedicated numerical model could support clinical and experimental strategies design and new VADs testing. The aim of this work is to perform a preliminary verification of a lumped parameter model of the cardiovascular system to simulate Fontan physiology and the effect of cavo-pulmonary assistance. Literature data of 4 pigs were used to simulate animals' baseline, and then the model was tested in simulating Fontan circulation and cavo-pulmonary-assisted condition comparing the simulation outcome (Sim) with measured literature data (Me). The results show that the numerical model can well reproduce experimental data in all three conditions (baseline, Fontan and assisted Fontan) [cardiac output (l/min): Me = 2.8 ± 1.7, Sim = 2.8 ± 1.8; ejection fraction (%): Me = 57 ± 17, Sim = 54 ± 17; arterial systemic pressure (mmHg): Me = 41.8 ± 18.6, Sim = 43.8 ± 18.1; pulmonary arterial pressure (mmHg): Me = 15.4 ± 8.9, Sim = 17.7 ± 9.9; caval pressure (mmHg): Me = 6.8 ± 4.1, Sim = 7 ± 4.6]. Systolic elastance, arterial systemic and arterial pulmonary resistances increase (10, 69, and 100 %) passing from the biventricular circulation to the Fontan physiology and then decrease (21, 39, and 50 %) once the VAD was implanted. The ventricular external work decreases (71 %) passing from the biventricular circulation to the Fontan physiology and it increases three times after the VAD implantation in parallel with the VAD power consumption. A numerical model could support clinicians in an innovative and challenging field as the use of VAD to assist the Fontan physiology and it could be helpful to personalize the VAD insertion on the base of ventricular systo-diastolic function, circulatory parameters and energetic variables.

Persistent pulmonary arterial hypertension in the newborn (PPHN): a frequent manifestation of TMEM70 defective patients.

INTRODUCTION: Mutations in the TMEM70 are the most common cause of nuclear ATP synthase deficiency resulting in a distinctive phenotype characterized by severe neonatal hypotonia, hypertrophic cardiomyopathy (HCMP), facial dysmorphism, severe lactic acidosis, hyperammonemia and 3-methylglutaconic aciduria (3-MGA). METHODS AND RESULTS: We collected 9 patients with genetically confirmed TMEM70 defect from 8 different families. Six were homozygous for the c.317-2A>G mutation, 2 were compound heterozygous for mutations c.317-2A>G and c.628A>C and 1 was homozygous for the novel c.701A>C mutation. Generalized hypotonia, lactic acidosis, hyperammonemia and 3-MGA were present in all since birth. Five patients presented acute respiratory distress at birth requiring intubation and ventilatory support. HCMP was detected in 5 newborns and appeared a few months later in 3 additional children. Five patients showed a severe and persistent neonatal pulmonary hypertension (PPHN) requiring Nitric Oxide (NO) and/or sildenafil administration combined in 2 cases with high-frequency oscillatory (HFO) ventilation. In 3 of these patients, echocardiography detected signs of HCMP at birth. CONCLUSIONS: PPHN is a life-threatening poorly understood condition with bad prognosis if untreated. Pulmonary hypertension has rarely been reported in mitochondrial disorders and, so far, it has been described in association with TMEM70 deficiency only in one patient. This report further expands the clinical and genetic spectrum of the syndrome indicating PPHN as a frequent and life-threatening complication regardless of the type of mutation. Moreover, in these children PPHN appears even in the absence of an overt cardiomyopathy, thus representing an early sign and a clue for diagnosis.

Coronary plaque composition assessed by intravascular ultrasound virtual histology: association with long-term clinical outcomes after heart transplantation in young adult recipients.

OBJECTIVES: To assess coronary plaque composition by virtual histology intravascular ultrasound (VH-IVUS) analysis in young adult recipients and to correlate these findings with time from heart transplant (HTx) and long-term outcomes. BACKGROUND: Rapid progression of coronary allograft vasculopathy after heart transplantation is a powerful predictor of mortality and clinical events at long-term. METHODS: Forty consecutive young adult recipients transplanted during childhood undergoing VH-IVUS during coronary surveillance have been prospectively included in this study. According to the time interval from HTx to VH-IVUS assessment, our cohort was divided into two groups (group A: ≤5 years, n = 13; group B: >5 years, n = 27). RESULTS: Group B showed an higher percentage of necrotic core and dense calcium (12 ± 2 vs. 5 ± 1%, P = 0.04; 8.2 vs. 2.1%, P = 0.03; respectively). An "inflammatory plaque" (necrotic core and dense calcium ≥30%) was detected in 34.8% of patients in group B and in none among group A patients (P = 0.03). Patients in group B had a number of adverse clinical events significantly higher than group A patients (53.8 vs. 14.3%; HR 4.45; 95% CI 1.62-12.16; P = 0.029) at long-term follow-up (4.2 years). The multivariate regression analysis showed that age (HR 1.5; 95% CI 1.1-2.0; P = 0.007), time from HTx (HR 1.8; 95% CI 1.6-4.8; P = 0.02), and inflammatory plaque (HR 2.4; 95% CI 1.1-5.3; P = 0.03) were independent predictors of adverse clinical events. CONCLUSIONS: This study supports the hypothesis that time-dependent differences in plaque composition, as assessed by VH-IVUS, occur after HTx in young adult recipients, probably determining an increased risk of long-term clinical events.

Lymphomonocytic inflammatory infiltrate with numerous eosinophilic granulocytes in the interstitium in a surviving heart transplant recipient: a case report.

Findings of eosinophilic and lymphomonocytic inflammatory infiltrates in endomyocardial biopsies (EMBs) may help in myocardial disease diagnosis identification. Eosinophilic myocarditis (EM), a rare condition, is fatal if left untreated and has rarely been described in heart transplant recipients. An extensive work up is necessary to achieve an early etiological diagnosis; however, the underlying cause remains unexplained in nearly one-third of the patients. The cornerstone of treatment is corticosteroids, comprehensive therapy and heart failure management (including advanced mechanical support for fulminant myocarditis). We have described the case of a 17-year-old heart transplant recipient who presented with a cardiogenic shock. He was admitted to our intensive care unit and treated with inotropic drugs, such as milrinone, adrenaline, vasopressin, and levosimendan; the doses of these drugs were in accordance with our internal protocol. The patient underwent cardiac catheterization, coronarography, and right ventricular EMB. EMB revealed inflammatory lymphomonocytic and eosinophil granulocyte infiltrates; thus, steroid therapy was initiated, with complete recovery achieved after 15 days. Performing an early differential diagnosis among eosinophilic infiltration, acute cellular rejection (ACR), and possible chemotherapeutic damage is emerging as an important challenge. To our knowledge, this is the first reported case of a lymphomonocytic inflammatory infiltration with numerous eosinophilic granulocytes in the interstitium in a surviving heart transplant recipient.

Neonatal persistent pulmonary hypertension related to a novel TBX4 mutation: case report and review of the literature.

TBX4 gene, located on human chromosome 17q23.2, encodes for T-Box Transcription Factor 4, a transcription factor that belongs to the T-box gene family and it is involved in the regulation of some embryonic developmental processes, with a significant impact on respiratory and skeletal illnesses. Herein, we present the case of a female neonate with persistent pulmonary hypertension (PH) who underwent extracorporeal membrane oxygenation (ECMO) on the first day of life and then resulted to have a novel variant of the TBX4 gene identified by Next-Generation Sequencing. We review the available literature about the association between PH with neonatal onset or emerging during the first months of life and mutations of the TBX4 gene, and compare our case to previously reported cases. Of 24 cases described from 2010 to 2023 sixteen (66.7%) presented with PH soon after birth. Skeletal abnormalities have been described in 5 cases (20%). Eleven cases (46%) were due to de novo mutations. Three patients (12%) required ECMO. Identification of this variant in affected individuals has implications for perinatal and postnatal management and genetic counselling. We suggest including TBX4 in genetic studies of neonates with pulmonary hypertension, even in the absence of skeletal abnormalities.

Ventricular assist device support in paediatric patients with restrictive cardiomyopathy - Clinical outcomes and haemodynamics.

OBJECTIVES: Restrictive cardiomyopathy is rare and is generally associated with worse clinical outcomes compared to other cardiomyopathies. Ventricular assist device support for these children is seldom applied and often hampered by the surgical difficulties. METHODS: All paediatric (<19 years) patients with a restricted cardiomyopathy supported by a ventricular assist device from the EUROMACS database were included and compared to patients with a dilated cardiomyopathy (retrospective database analyses). Participating centres were retrospectively contacted to provide additional detailed echo and Swan Ganz measurements to analyse the effect of ventricular assist device support on pulmonary artery pressure and right ventricular function. RESULTS: Forty-four paediatric ventricular assist device-supported patients diagnosed with restricted cardiomyopathy were included, with a median age at implantation of 5.0 years. Twenty-six of the 44 patient with a restricted cardiomyopathy survived to transplantation (59.1%), 16 died (36.4%) and 2 are still on ongoing VAD support (4.5%) after a median duration of support of 95.5 days (IQR 33.3-217.8). Transplantation probability after 1 and 2 years of ventricular assist device support in patients with a restricted cardiomyopathy were comparable to patients with a dilated cardiomyopathy (52.3% vs 51.4% and 59.5% vs 60.1%, p = 0.868). However, mortality probability was higher in the restricted cardiomyopathy cohort (35.8% vs 17.0% and 35.8% vs 19.0%, p = 0.005). Adverse event rates were high (CVA in 31.8%, pump thrombosis in 29.5%, major bleeding 25.0%, eventual biventricular support in 59.1%). In the atrially cannulated group, CVA and pump thrombosis occurred in twice as much patients (21.1% vs 40.0%, p = 0.595 and 15.8% vs 40.0%, p = 0.464; probably non-significant due to the small numbers). Pulmonary arterial pressures improved after implantation of a ventricular assist device, and six patients who were initially labelled as ineligible due to pulmonary hypertension could eventually be transplanted. CONCLUSIONS: Ventricular assist device support in children with a restricted cardiomyopathy is rarely performed. Mortality and adverse event rates are high. On the other hand, survival to cardiac transplantation was 59.1% with all patients surviving the first 30 days after cardiac transplantation. Pulmonary arterial pressures improved while on support, potentially making cardiac transplantation a viable option for previously ineligible children.

Remember Friedreich ataxia even in a toddler with apparently isolated dilated (not hypertrophic!) cardiomyopathy. Revisited.

Friedreich ataxia (FRDA) is the most common form of ataxia in late childhood. Neurological manifestations often precede cardiac involvement, presenting mainly as hypertrophic cardiomyopathy. We describe a toddler with apparently isolated severe heart failure, successfully managed with heart transplant (HT). Although well described in adolescents and adults, onset of FRDA is very uncommon in toddlers and neurological ataxic features are predominant. The presenting symptom of cardiomyopathy is very rare. Similar history is rarely reported in literature, that we described, including an aggressive cardiomyopathy in children younger than 5 years-old. RESULTS: Our patient was diagnosed with FRDA at a postoperative stage due to minimal neurological manifestations. Moreover, the novelty of this study lies in demonstrating a major DNA triplet repeat expansion in skeletal muscle compared to DNA from peripheral blood leukocytes. These results support the concept that triplet repeat expansion is variable among different tissues in FRDA, and in our case it was more expanded in the post mitotic muscular tissue than in blood cells. We believe on the importance of taking in consideration this rare condition even in a toddler with apparently isolated cardiomyopathy and especially when conventional investigations give negative results. We discuss potential trigger effect of HT as a precipitating factor in manifesting neurological symptoms. This observation corresponds to our experience and relates to three patients described so far (the third patient died suddenly). Early onset cardiomyopathy with FRDA should increase awareness of this rare condition and we highlight HT successful outcome. Further reports are needed to delineate this rare condition in youngsters.

Continuitiy of care with ataluren in Duchenne Muscular Dystrophy patients with nonsense mutations after loss of ambulation. Personal experience.

Duchenne Muscular Dystrophy (DMD) includes predictable phases requiring dedicated standard treatments. Therapeutic strategies feature corticosteroids or the more recent gene therapy/stop codon read-through. Ataluren (Translarna®) is an oral drug promoting the readthrough of premature stop codons caused by nonsense mutation (nm) in order to produce full-length dystrophin. It was licensed by EMA in 2014 for ambulatory patients with nmDMD aged ≥ 5 years. Our aim is to report data on long-term ataluren use in Italian patients with nmDMD, with emphasis on continuity of the treatment after loss of ambulation (LoA). Four DMD patients aged between 16 and 24 years who lost ambulation between 12 and 14 years continued to take ataluren after LoA. The oldest patient, aged 24 years, is still taking a few steps. Even in those experiencing motor decline, PUL-test performances were stable and respiratory function satisfactory in all; two patients developed severe cardiomyopathy, stable in one. Therapeutic continuity with ataluren should be offered to all nmDMD patients after LoA given its favourable safety and efficacy profile. However, further research is recommended to identify additional clinically meaningful outcomes and treatment goals following LoA.

Apixaban for Prevention of Thromboembolism in Pediatric Heart Disease.

BACKGROUND: Children with heart disease frequently require anticoagulation for thromboprophylaxis. Current standard of care (SOC), vitamin K antagonists or low-molecular-weight heparin, has significant disadvantages. OBJECTIVES: The authors sought to describe safety, pharmacokinetics (PK), pharmacodynamics, and efficacy of apixaban, an oral, direct factor Xa inhibitor, for prevention of thromboembolism in children with congenital or acquired heart disease. METHODS: Phase 2, open-label trial in children (ages, 28 days to <18 years) with heart disease requiring thromboprophylaxis. Randomization 2:1 apixaban or SOC for 1 year with intention-to-treat analysis. PRIMARY ENDPOINT: a composite of adjudicated major or clinically relevant nonmajor bleeding. Secondary endpoints: PK, pharmacodynamics, quality of life, and exploration of efficacy. RESULTS: From 2017 to 2021, 192 participants were randomized, 129 apixaban and 63 SOC. Diagnoses included single ventricle (74%), Kawasaki disease (14%), and other heart disease (12%). One apixaban participant (0.8%) and 3 with SOC (4.8%) had major or clinically relevant nonmajor bleeding (% difference -4.0 [95% CI: -12.8 to 0.8]). Apixaban incidence rate for all bleeding events was nearly twice the rate of SOC (100.0 vs 58.2 per 100 person-years), driven by 12 participants with ≥4 minor bleeding events. No thromboembolic events or deaths occurred in either arm. Apixaban pediatric PK steady-state exposures were consistent with adult levels. CONCLUSIONS: In this pediatric multinational, randomized trial, bleeding and thromboembolism were infrequent on apixaban and SOC. Apixaban PK data correlated well with adult trials that demonstrated efficacy. These results support the use of apixaban as an alternative to SOC for thromboprophylaxis in pediatric heart disease. (A Study of the Safety and Pharmacokinetics of Apixaban Versus Vitamin K Antagonist [VKA] or Low Molecular Weight Heparin [LMWH] in Pediatric Subjects With Congenital or Acquired Heart Disease Requiring Anticoagulation; NCT02981472).