High-Throughput Genomics Identify Novel FBN1/2 Variants in Severe Neonatal Marfan Syndrome and Congenital Heart Defects.

Fibrillin-1 and fibrillin-2, encoded by FBN1 and FBN2, respectively, play significant roles in elastic fiber assembly, with pathogenic variants causing a diverse group of connective tissue disorders such as Marfan syndrome (MFS) and congenital contractural arachnodactyly (CCD). Different genomic variations may lead to heterogeneous phenotypic features and functional consequences. Recent high-throughput sequencing modalities have allowed detection of novel variants that may guide the care for patients and inform the genetic counseling for their families. We performed clinical phenotyping for two newborn infants with complex congenital heart defects. For genetic investigations, we employed next-generation sequencing strategies including whole-genome Single-Nucleotide Polymorphism (SNP) microarray for infant A with valvular insufficiency, aortic sinus dilatation, hydronephrosis, and dysmorphic features, and Trio whole-exome sequencing (WES) for infant B with dextro-transposition of the great arteries (D-TGA) and both parents. Infant A is a term male with neonatal marfanoid features, left-sided hydronephrosis, and complex congenital heart defects including tricuspid regurgitation, aortic sinus dilatation, patent foramen ovale, patent ductus arteriosus, mitral regurgitation, tricuspid regurgitation, aortic regurgitation, and pulmonary sinus dilatation. He developed severe persistent pulmonary hypertension and worsening acute hypercapnic hypoxemic respiratory failure, and subsequently expired on day of life (DOL) 10 after compassionate extubation. Cytogenomic whole-genome SNP microarray analysis revealed a deletion within the FBN1 gene spanning exons 7-30, which overlapped with the exon deletion hotspot region associated with neonatal Marfan syndrome. Infant B is a term male prenatally diagnosed with isolated D-TGA. He required balloon atrial septostomy on DOL 0 and subsequent atrial switch operation, atrial septal defect repair, and patent ductus arteriosus ligation on DOL 5. Trio-WES revealed compound heterozygous c.518C>T and c.8230T>G variants in the FBN2 gene. Zygosity analysis confirmed each of the variants was inherited from one of the parents who were healthy heterozygous carriers. Since his cardiac repair at birth, he has been growing and developing well without any further hospitalization. Our study highlights novel FBN1/FBN2 variants and signifies the phenotype-genotype association in two infants affected with complex congenital heart defects with and without dysmorphic features. These findings speak to the importance of next-generation high-throughput genomics for novel variant detection and the phenotypic variability associated with FBN1/FBN2 variants, particularly in the neonatal period, which may significantly impact clinical care and family counseling.

Cell-free DNA blood test for the diagnosis of pediatric tuberculous meningitis.

Pediatric tuberculous meningitis (TBM) is a severe form of tuberculosis that may present in children. The current diagnostic methods may have a limited impact on initial clinical decision-making. We present three children with tuberculous meningitis who had Mycobacterium tuberculosis complex cell-free DNA (cfDNA) detected in their blood within three days of sampling. Our cases described here illustrate for the first time the potential role of cfDNA blood tests in the rapid diagnosis of TBM.

Decompressive Hemicraniectomy and Favorable Outcome in a Pediatric Patient with Malignant Middle Cerebral Artery Infarction.

We report a rare case of middle cerebral artery (MCA) stroke in a teenage girl with initial improvement, followed by progression to malignant MCA infarction, requiring an urgent decompressive hemicraniectomy (DHC). Additionally, we report improvement in all areas, including language, comprehension, and motor skills at discharge and the 4-month follow-up. This rare presentation highlights the importance of monitoring the neurological status of a patient with an MCA infarct for progression to a life-threatening malignant MCA infarct. This case report also highlights the importance of consideration of DHC for a favorable outcome of the MMCA infarction.

Angiotensin converting enzyme 2 and angiotensin (1-7) axis in pulmonary arterial hypertension.

BACKGROUND: In animal models of pulmonary arterial hypertension (PAH), angiotensin-converting enzyme (ACE)2 and angiotensin (Ang)-(1-7) have been shown to have vasodilatory, antiproliferative, antifibrotic and antihypertrophic properties. However, the status and role of the ACE2-Ang(1-7) axis in human PAH is incompletely understood. METHODS: We studied 85 patients with a diagnosis of PAH of distinct aetiologies. 55 healthy blood donors paired for age and sex served as controls. Blood samples were obtained from the pulmonary artery in patients with PAH during right heart catheterisation. Peripheral blood was obtained for both groups. Ang(1-7) and -II were measured using zone capillary electrophoresis. Aldosterone, Ang(1-9), AngA and ACE2 were measured using ELISA, and ACE2 activity was determined enzymatically. RESULTS: Of the 85 patients, 47 had idiopathic PAH, 25 had PAH associated with congenital heart disease and 13 had PAH associated with collagen vascular disease. Compared to controls, patients with PAH had a higher concentration of AngII (median 1.03, interquartile range 0.72-1.88 pmol·mL-1 versus 0.19, 0.10-0.37 pmol·mL-1; p<0.001) and of aldosterone (88.7, 58.7-132 ng·dL-1 versus 12.9, 9.55-19.9 ng·dL-1; p<0.001). Conversely, PAH patients had a lower concentration of Ang(1-7) than controls (0.69, 0.474-0.91 pmol·mL-1 versus 4.07, 2.82-6.73 pmol·mL-1; p<0.001), and a lower concentration of Ang(1-9) and AngA. Similarly, the ACE2 concentration was higher than in controls (8.7, 5.35-13.2 ng·mL-1 versus 4.53, 1.47-14.3 ng·mL-1; p=0.011), whereas the ACE2 activity was significantly reduced (1.88, 1.08-2.81 nmol·mL-1 versus 5.97, 3.1-17.8 nmol·mL-1; p<0.001). No significant differences were found among the three different aetiological forms of PAH. CONCLUSIONS: The AngII-ACE2-Ang(1-7) axis appears to be altered in human PAH and we propose that this imbalance, in favour of AngII, plays a role in the pathogenesis of the severe PAH. Further mechanistic studies are warranted.

Sleep endoscopy-directed management of Arnold-Chiari malformation: a child with persistent obstructive sleep apnea.

None: Arnold-Chiari malformations are structural defects in the base of the skull and cerebellum, when part of the cerebellar tonsils herniates through the foramen magnum into the upper spinal canal, compressing against the brainstem. This anatomical defect can be asymptomatic but often presents with symptoms such as headaches, stridor, dysphagia, and nystagmus. It also presents with a variety of sleep-related breathing disorders such as snoring, obstructive sleep apnea, central sleep apnea, bradypnea, and sleep hypoventilation. Sometimes these conditions can coexist in one patient. Although obstructive sleep apnea can be a manifestation of Arnold-Chiari malformation, identifying causality and the site of obstruction in these children can be a diagnostic challenge. We review the case of a 14-month-old male who presented with noisy breathing and obstructive sleep apnea diagnosed on sleep study that was refractory to initial upper airway surgery. Although a brain computed tomography scan done in the emergency room for altered mental status revealed a type 1 Arnold-Chiari malformation, and a flexible awake laryngoscopy was normal, subsequent drug-induced sleep endoscopy was helpful in justifying surgical decompression of the Arnold-Chiari malformation that resulted in complete resolution of the obstructive sleep apnea.

Fluid Infusion Through Chest Tube to Facilitate Pleural Procedures: A Feasibility Study.

BACKGROUND: Most pleural procedures need the presence of a moderate effusion to allow safe access to the pleural space. We propose a technique to allow safe access in patients with a drained pleural space who require further pleural evaluation or treatment during the same hospital stay. METHODS: This was a retrospective study. All patients who underwent any pleural intervention with a prior infusion of fluid in the pleural space using a pre-existing chest tube (≤14 Fr) were included. Before the pleural intervention, warm saline was infused into the pleural space through the small-bore chest tube until enough fluid was detected on thoracic ultrasound to allow pleural access. Data on patient demographics, indication for the pleural procedure, and patient outcome was analyzed. RESULTS: A total of 22 patients with pleural disease underwent definitive pleural procedure facilitated by fluid infusion. Median volume of fluid infused was 1000 mL (850, 1500 mL). The median time between the initial chest tube insertion and the subsequent definitive pleural procedure was 3 days (2, 7 d). All procedures were completed successfully. One patient had a hemothorax secondary to fluid infusion. CONCLUSION: Fluid infusion through a chest tube is a feasible technique for patients that require a pleural procedure and have minimal fluid after initial pleural drainage. This approach may facilitate pleural procedures, reduce incidence of complications, and expedite the diagnosis and treatment of patients with pleural diseases. Pressure infusers should not be used during this procedure as there is a theoretical increased risk of complications.

Advances in medical therapy for pulmonary arterial hypertension.

PURPOSE OF REVIEW: The purpose of this review is to demonstrate advances in the medical treatment of pulmonary arterial hypertension (PAH). Reviewed will be the evidence that favors the use of risk assessment in the treatment of PAH. Optimization of combination therapy depending on the risk or worsening will be reviewed. Finally, recent advances in new treatment strategies will be mentioned. RECENT FINDINGS: The use of therapies in sequence or in combination for the treatment of PAH has been shown to decrease morbidity and mortality. Tailoring these treatment strategies to a risk of worsening has been shown to decrease mortality and time to clinical worsening because of PAH. In addition, there have been several advances in the development of other medications separate from the three known pathogenic pathways in PAH. SUMMARY: In the last 15 years, 12 specific therapies have been approved for PAH. These therapies target three separate pathogenic pathways [the endothelin (ET), nitric oxide (NO) and prostacyclin (PGI2)]. As a result, treatment guidelines have tailored the treatment of PAH with these medications either as single drug therapy or in combination. Recently, other treatment pathways have been explored as new strategies for the treatment of PAH.

Algo se puede decir sobre la articulación de las perversiones y las adicciones / Something can be said about the articulation of addictions and perversions / On peut dire quelque chose sur l'articulation de las perversions et les dépendances

Consideramos que la perversión y las adicciones evidencian diferentes formas de patología narcisista y serían soluciones secundarias a algunos traumatismos primarios que han afectado a la organización primitiva de la identidad y al narcisismo primario. Lo traumático sería lo no simbolizado. La perversión busca una salida resexualizando lo no representado y la adicción suple una representación no establecida dentro mediante un obJeto externo perceptivo, la droga. Animados por el trabajo clínico con un paciente cuyo psiquismo presenta a la vez ambas soluciones al vacío representativo, lo perverso y lo adictivo, nos planteamos escribir este artículo

We consider that perversion and addictions are different forms of narcissistic pathology and, as such, consist of secondary solutions to sorne kinds of primary traumatisms that have affected the primitive organization of identity and primary narcissism. The traumatic would be what is not symbolized. The perversion looks for an outlet, resexualizing what is not represented and addiction compensates for a representation not present within through an external perceptive object, the drug. Encouraged by the clinical work carried out on a patient whose psyche simultaneously represents both solutions to this representative void, the perverse and the addictive, we decided to write this article

Nous considérons que la perversion et les dépendances présentent des formes diff érentes d'une pathologie narcissiste et consisteraient en solutions secondaires a quelques traumatismes primaires qui ont aff ecté á l' organisation primitive de l'identité et au narcissisme primaire. Le traumatique serait le nom symbolisé. La perversion cherche une sortie resexualisée le non représenté et la toxicomanie remplace a une représentation non établie a l'intérieur au moyen d'un objet externe perceptuel, la drogue. Animés par le travail clinique avec un patient dont le psychisme présente a la fois les deux solutions au vide représentatif: le pervers et l' addictive, nous nous posons écrire cet article