Genetics has assumed a pivotal role in clarifying the pathophysiology of cardiomyopathies, facilitating molecular diagnosis, and enabling effective family screening. The advent of next-generation sequencing has revolutionized genetic testing by enabling cost-effective, high-throughput analysis. It is imperative for cardiovascular physicians to mainstream genetic testing into their clinical decision-making. Although a definitive genotype-phenotype correlation may not always be evident, several genotypes have emerged as valuable risk predictors for disease severity and progression. European guidelines emphasize the importance of genetic tests for predicting clinical outcome in cardiomyopathies. While further research is essential to bridge existing gaps in the genetic evidence on cardiomyopathies, there is considerable potential for significant advancements.

Cardiomyopathies may present as a manifestation of various inherited syndromes. Recognizing the rarity and diagnostic challenges of syndromic and metabolic cardiomyopathies is crucial, as their identification holds significant implications for targeted treatment and enables the use of specific risk stratification tools. Genetics has assumed a pivotal role in clarifying the pathophysiology of cardiomyopathies, facilitating molecular diagnosis, and enabling effective family screening. The advent of next-generation sequencing has revolutionized genetic testing, enabling cost-effective, high-throughput analyses, facilitating the diagnosis of these rare conditions, and allowing the provision of specific management and therapeutics.

Background:Neurofibromatosis type 1 (NF1) is a common genetic disorder of phenotypic variability with age-dependent penetrance. This study describes the diagnosis, clinical characterization, management, and outcomes of a large patient cohort with plexiform neurofibroma (PN) treated with selumetinib in a real-world clinical setting. Methods:This single-center observational study consecutively enrolled patients with NF1-PN treated with selumetinib from April 2018 to 2023. Data on clinical features, tumor types and locations, and results from genetic tests were recorded at baseline; details of disease management with selumetinib and surgical intervention and disease evolution including imaging data and evaluations of pain and function were documented. Results:Overall, 54 patients with a median age (range) of 16.4 (4.5-58.0) years were enrolled. Most had cutaneous manifestations (88.9%), including cutaneous neurofibromas and PN. Patients underwent [18F]fluorodeoxyglucose (FDG)-PET/CT imaging before treatment to rule out malignant lesions. Initial evaluations included directed magnetic resonance imaging (MRI), which facilitated future comparisons and allowed for the assessment of PN resectability. Pharmacological treatment with selumetinib (with surgery, without surgery) resulted in the following proportion of patients achieving stable disease (58.8%, 54.3%), partial response (29.4%, 28.6%), and improved pain (58.8%, 37.1%), deformity (17.6%, 20.0%), and functional (17.6%, 20.0%) outcomes, respectively. Conclusions:Results from this study demonstrate that NF1-PN can be managed effectively with selumetinib with surgical intervention in some patients. Most patients achieved tumor stability and improved symptom control, and the majority of patients continue under treatment. Effective diagnosis and management were achieved through individualized utility of FDG-PET/CT and MRI imaging and targeted resource allocation.

Neurofibromatosis type 2 (NF2) is a brain tumor predisposing syndrome caused by inactivating alterations of the NF2 gene mapped at chromosome 22q. Currently, no genetic information exists on medulloblastomas occurring in NF2 patients. We herein report on the genetic alterations observed in a girl in which the NF2 gene was de novo altered due to a constitutional translocation: t(5;22)(q35.1;q11.2). This girl had a particularly aggressive disease course. At the age of 4, she had already been diagnosed with three lesions classified as schwannomas and a meningioma. At 10 years old, she developed a medulloblastoma. She died at the age of 14 due to a refractory acute myeloid leukemia (AML). From the genetic point of view, we observed that (1) the NF2 gene was rearranged in all patient samples: blood, tumor, and leukemic cells; (2) loss of 3' region of NF2 and the downstream regions of chromosome 22 were only detected in medulloblastoma cells; (3) the known cancer AML-related gene: NPM1 which is mapped at 5q35.1 was not the target of any alteration in our patient. Our data suggest that inactivation of the NF2 gene was relevant for the medulloblastoma pathogenesis. Furthermore, we know that malignant cancers are the result of a multi-epi-genetic sequence of events, and although, unquestionably limited to the genetic findings in one case. We may hypothesize, that as described for a fraction of medulloblastomas, the alteration of a gene mapped at 5q might also have been relevant for medulloblastoma development in our patient.

Cerebral cavernous malformations (CCMs) are vascular malformations characterized by the abnormal growth of vascular structures in the central nervous system. However, the precise mechanism(s) responsible for the development of CCM vascular abnormalities remain poorly understood. Although the mechanisms of action of propranolol in CCM have not yet been fully explored it is not commonly prescribed, it has been shown to be effective in children and appears to play a protective role in the prevention of CCM‑derived hemorrhage in adults. The present study performed in vitro and ex vivo assays in order to examine the effects of propranolol on endothelial cells (ECs). The percentage of CD14+/CD31+ cells and the levels of VEGF in the peripheral blood (PB) of a child patient with CCM, with recurrent seizures and hemorrhages, who was maintained under propranolol therapy, were also analyzed. In addition to the effects of propranolol on differentiated ECs, and the decrease angiogenic‑related features in vitro and ex vivo, it was observed that in the PB of this patient, propranolol administration decreased the percentage of circulating cells sharing monocytic and EC features (CD14+/CD31+ cells), as well as the VEGF levels; this was concomitant with a good prognosis and with the reversion of CCM lesions. A decrease in VEGF levels by propranolol may also be involved in the impairment of the recruitment of CD14+/CD31+ monocytes functioning as endothelial progenitor cells to sustain the vascular lesion. On the whole, the present study demonstrates that propranolol impairs angiogenesis in vitro and may thus be a useful tool for the clinical management of CCM. Moreover, the present study highlights the monitorization of the levels of CD14+/CD31+ monocytes and VEGF levels as a useful tool for predicting the clinical efficacy of propranolol in patients with CCM.

There is little knowledge on the pathophysiology of pediatric stroke associated with radiation-induced occlusive cerebral vasculopathy (RIOCV). Herein, we present an extremely rare case of a child with multiple ischemic strokes in association with progressive RIOCV. The possibility of hemodynamic compromise and artery-to-artery embolism as a cause of the ischemic events is discussed.

Background: Diffuse midline glioma (DMG) is one of the most aggressive pediatric tumors. Approximately 60% of pediatric DMG patients die within the first year of diagnosis. Complete clinical and radiological remission of DMG is extremely rare. The objective of this study was to describe a case of remission of pediatric DMG and to compare with similar cases published so far. Results: DMG was diagnosed in a 2-year-old girl who presented with brainstem and increased intracranial pressure manifestations. Ventriculoperitoneal shunt and chemotherapy-based treatment were offered. From the diagnosis, in spite of progressive enlargement of the tumoral lesion, her clinical condition improved remarkably. After the end of chemotherapy, progressive and gradual imagiological improvements occurred. At the end of the 60th month of follow-up, she was asymptomatic with total remission. Six pediatric DMG cases, from birth to the age of 3, in whom remission occurred were found in the literature. Histology sample was available in two of them (fibrillary astrocytoma-WHO Grade II and anaplastic astrocytoma-WHO Grade III). None received chemotherapy or radiotherapy. Conclusion: Remission of pediatric DMG is extremely rare and reinforces the biological heterogeneity of the tumor. In the absence of reliable predictors of prognosis, offering the best supportive treatment, including neurosurgical interventions should be considered in similar cases.

Plexiform neurofibromas (PN) are the most frequent tumors associated with Neurofibromatosis type 1 (NF-1). PN can cause significant complications, including pain, functional impairment, and disfigurement. There is no efficient medical treatment and, surgical resection of large PN is frequently infeasible. Selumetinib (AZD6244/ARRY-142886) is a mitogen-activated protein kinase enzyme (MEK1/2) inhibitor and works by targeting the MAPK pathway. It is an investigational treatment option for inoperable symptomatic PN associated with NF-1. Herein, we describe a single institutional experience with selumetinib for inoperable PN in NF-1. Case series study of demographics, clinical, baseline characteristics, treatment effect, and follow-up of consecutive genetically confirmed NF1 patients with inoperable PN associated with significant or potential significant morbidity treated with selumetinib (April 2018 to April 2019). Nineteen patients were treated with selumetinib. Predominant target locations were head and neck (31.6%, 6/19), chest (26.3%, 5/19) and pelvis (21%, 4/19) and the most important comorbidities were disfigurement (47.4%, 9/19) and pain (26.3%, 5/19). The mean follow-up time was 223 days (range 35–420 days). All but one had sustained clinical improvement, mainly in the first 60–90 days of treatment. In one patient, the treatment was suspended after 168 days (lack of clear benefit and left ventricular ejection fraction drop). There were no adverse effects leading to treatment suspension. In the first observational study of selumetinib for NF-1 associated PN we showed that the drug was associated with clinical and radiological improvement. Our study also confirms the safety described in the clinical trials.