Ictus asociado a cáncer: estudio de prevalencia y factores predictores entre pacientes con ictus isquémico / Cancer-associated stroke: a study of prevalence and predictors among ischaemic stroke patients

Introducción: La asociación entre cáncer e ictus está bien documentada y conlleva un peor pronóstico de ambas patologías. Sin embargo, la prevalencia de cáncer activo y cáncer oculto entre pacientes con ictus no está suficientemente establecida, ni tampoco los factores predictores al ictus asociado al cáncer. Su conocimiento es importante para una mejor identificación y optimización del tratamiento de estos pacientes. Pacientes y métodos: El objetivo de este estudio retrospectivo es analizar las características del ictus isquémico, en pacientes con y sin cáncer activo, en una muestra de pacientes ingresados durante dos años en una unidad de ictus. Se realiza un análisis descriptivo general y de casos y controles, para evaluar las diferencias entre ambos grupos. Resultados: En una muestra de 616 pacientes con ictus isquémico se encontró una prevalencia de cáncer del 19,2%, que era activo (previo o diagnosticado tras el ictus) en un 7,5%. El cáncer activo se asoció con el hallazgo de lesiones en varios territorios vasculares, valores más bajos de hemoglobina y hematocrito, y más altos de fibrinógeno y proteína C reactiva, tendencia a peor situación funcional y mayor mortalidad a los tres meses. Conclusiones: Se encontró una alta prevalencia de cáncer sistémico, de cualquier tipo, y también activo y oculto, entre pacientes con ictus isquémico. La presencia de lesiones isquémicas en varios territorios vasculares y algunos marcadores de laboratorio podrían ser factores que habría que considerar para atribuir el ictus al cáncer o buscar una neoplasia oculta en algunos pacientes.(AU)

Introduction: The association between cancer and stroke is well documented and entails a worse prognosis for both pathologies. However, the prevalence of active and occult cancer among stroke patients is not sufficiently established, and neither are the predictors of cancer-associated stroke. Their knowledge is important for better identification and optimisation of the treatment of these patients. Patients and methods: The aim of this retrospective study is to analyse the characteristics of ischaemic stroke in patients with and without active cancer in a sample of patients admitted to a stroke unit for two years. An overall descriptive and case-control analysis is performed to assess the differences between the two groups. Results: In a sample of 616 patients with ischaemic stroke, a prevalence of cancer was found to be 19.2%, which was active (prior or diagnosed after the stroke) in 7.5% of them. Active cancer was associated with the finding of lesions in several vascular territories, lower haemoglobin and haematocrit values, and higher fibrinogen and C-reactive protein values, a tendency to worse functional status and higher mortality at three months. Conclusions: A high prevalence of systemic cancer, of any type, as well as active and occult, was found among patients with ischaemic stroke. The presence of ischaemic lesions in several vascular territories and some laboratory markers could be factors to consider in attributing the stroke to cancer or looking for an occult neoplasm in some patients.(AU)

Case report: ETS1 gene deletion associated with a low number of recent thymic emigrants in three patients with Jacobsen syndrome.

Jacobsen syndrome is a rare genetic disorder associated with a terminal deletion in chromosome 11. The clinical presentation is variable. Although immunodeficiency has been described in patients with Jacobsen syndrome, a clear genotype-phenotype correlation has not yet been established. Here, we report on the immunologic phenotypes of four patients with Jacobsen syndrome. All four patients showed one or more atypical immunologic features. One patient suffered from recurrent viral infections, two patients had experienced a severe bacterial infection and one had received antibiotic prophylaxis since early childhood. One patient had experienced severe, transient immune dysregulation. Hypogammaglobulinemia and low B cell counts were found in two patients, while the number of recent thymic emigrants (CD31+CD45RA+ CD4 cells) was abnormally low in three. When considering the six immune-related genes located within the affected part of chromosome 11 (ETS1, TIRAP, FLI1, NFRKB, THYN1, and SNX19), only the ETS1 gene was found be deleted in the three patients with low numbers of recent thymic emigrants and non-switched memory B cells. Our findings support the hypothesis whereby Jacobsen syndrome is associated with a combined immunodeficiency with variable presentation. Further investigations of potential genotype-phenotype correlations are warranted and might help to personalize patient management in individuals lacking immune-related genes. In addition, we recommend immunologic follow-up for all patients with Jacobsen syndrome, as immune abnormalities may develop over time.

Deletion of 11q24.2-qter in a male child with cleft lip and palate: an atypical feature of Jacobsen syndrome.

Jacobsen syndrome (JS) is caused by the terminal deletion at the long arm of chromosome 11. It is characterized by growth retardation, intellectual disability, facial dysmorphism, and other congenital abnormalities. The subband 11q24.1 has been confirmed to be the critical region for the typical features of JS. The patient in the current study is a 2-year-old male child with prominent craniofacial abnormalities and congenital heart disease. High-resolution single-nucleotide polymorphism arrays revealed breakage in chromosome 11q beginning at 11q24.2, with complete deletion of the distal portion. We collected all available reports describing patients with breakages at 11q24.1 or 11q24.2, and compared it with the typical features of JS. We found that the phenotype of cleft lip and palate (CLP) was present in both groups of patients with no overlap region in the deletion region (between 11q21-q23 and 11q24.2-qter), which indicated that other genes may be related to CLP in JS.

Endothelial Loss of ETS1 Impairs Coronary Vascular Development and Leads to Ventricular Non-Compaction.

RATIONALE: Jacobsen syndrome is a rare chromosomal disorder caused by deletions in the long arm of human chromosome 11, resulting in multiple developmental defects including congenital heart defects. Combined studies in humans and genetically engineered mice implicate that loss of ETS1 (E26 transformation specific 1) is the cause of congenital heart defects in Jacobsen syndrome, but the underlying molecular and cellular mechanisms are unknown. OBJECTIVE: To determine the role of ETS1 in heart development, specifically its roles in coronary endothelium and endocardium and the mechanisms by which loss of ETS1 causes coronary vascular defects and ventricular noncompaction. METHODS AND RESULTS: ETS1 global and endothelial-specific knockout mice were used. Phenotypic assessments, RNA sequencing, and chromatin immunoprecipitation analysis were performed together with expression analysis, immunofluorescence and RNAscope in situ hybridization to uncover phenotypic and transcriptomic changes in response to loss of ETS1. Loss of ETS1 in endothelial cells causes ventricular noncompaction, reproducing the phenotype arising from global deletion of ETS1. Endothelial-specific deletion of ETS1 decreased the levels of Alk1 (activin receptor-like kinase 1), Cldn5 (claudin 5), Sox18 (SRY-box transcription factor 18), Robo4 (roundabout guidance receptor 4), Esm1 (endothelial cell specific molecule 1) and Kdr (kinase insert domain receptor), 6 important angiogenesis-relevant genes in endothelial cells, causing a coronary vasculature developmental defect in association with decreased compact zone cardiomyocyte proliferation. Downregulation of ALK1 expression in endocardium due to the loss of ETS1, along with the upregulation of TGF (transforming growth factor)-ß1 and TGF-ß3, occurred with increased TGFBR2/TGFBR1/SMAD2 signaling and increased extracellular matrix expression in the trabecular layer, in association with increased trabecular cardiomyocyte proliferation. CONCLUSIONS: These results demonstrate the importance of endothelial and endocardial ETS1 in cardiac development. Delineation of the gene regulatory network involving ETS1 in heart development will enhance our understanding of the molecular mechanisms underlying ventricular and coronary vascular developmental defects and will lead to improved approaches for the treatment of patients with congenital heart disease.

Patients with Chromosome 11q Deletions Are Characterized by Inborn Errors of Immunity Involving both B and T Lymphocytes.

Disorders of the long arm of chromosome 11 (11q) are rare and involve various chromosomal regions. Patients with 11q disorders, including Jacobsen syndrome, often present with a susceptibility for bacterial and prolonged viral and fungal infections partially explained by hypogammaglobulinemia. Additional T lymphocyte or granular neutrophil dysfunction may also be present. In order to evaluate infectious burden and immunological function in patients with 11q disorders, we studied a cohort of 14 patients with 11q deletions and duplications. Clinically, 12 patients exhibited prolonged and repetitive respiratory tract infections, frequently requiring (prophylactic) antibiotic treatment (n = 7), ear-tube placement (n = 9), or use of inhalers (n = 5). Complicated varicella infections (n = 5), chronic eczema (n = 6), warts (n = 2), and chronic fungal infections (n = 4) were reported. Six patients were on immunoglobulin replacement therapy. We observed a high prevalence of low B lymphocyte counts (n = 8), decreased T lymphocyte counts (n = 5) and abnormal T lymphocyte function (n = 12). Granulocyte function was abnormal in 29% without a clinical phenotype. Immunodeficiency was found in patients with terminal and interstitial 11q deletions and in one patient with terminal 11q duplication. Genetically, FLI1 and ETS1 are seen as causative for the immunodeficiency, but these genes were deleted nor duplicated in 4 of our 14 patients. Alternative candidate genes on 11q may have a role in immune dysregulation. In conclusion, we present evidence that inborn errors of immunity are present in patients with 11q disorders leading to clinically relevant infections. Therefore, broad immunological screening and necessary treatment is of importance in this patient group.

Neonatal interstitial lung disease in a girl with Jacobsen syndrome: a case report.

BACKGROUND: We report a case of the neonatal interstitial lung disease pulmonary interstitial glycogenosis in a girl with Jacobsen syndrome. While Jacobsen syndrome is caused by a deletion on the long arm of chromosome 11 and is genetically confirmed, pulmonary interstitial glycogenosis is of unknown etiology and is diagnosed by lung biopsy. Pulmonary interstitial glycogenosis has not previously been described in association with Jacobsen syndrome. CASE PRESENTATION: A term newborn small for gestational age Caucasian girl presented with respiratory distress, pulmonary hypertension, congenital heart defects, immunodeficiency, and thrombocytopenia. She was diagnosed with Jacobsen syndrome, but also had pulmonary interstitial glycogenosis, which contributed to significant morbidity. There was striking clinical improvement after steroid treatment of the pulmonary interstitial glycogenosis. CONCLUSIONS: Interstitial lung disease should be considered as a differential diagnosis when respiratory distress and hypoxemia in the perinatal period worsens or persists despite standard treatment. Importantly, pulmonary interstitial glycogenosis may be treatable with corticosteroids. Whether there is a genetic link between pulmonary interstitial glycogenosis and Jacobsen syndrome is still unknown.

Prenatal Identification and Confirmation of Jacobsen Syndrome: A Series of Four Cases.

Jacobsen syndrome (JBS) is a rare contiguous gene disorder caused by partial deletion of the distal part of the long arm of chromosome 11. Only a few prenatal cases of JBS have been reported, and data on prenatal ultrasonographic findings are relatively scarce. We analysed four cases of JBS diagnosed prenatally in our centre. All four cases received ultrasound examination in the second trimester. Cardiac defects and intrauterine growth retardation (IUGR) were present in three cases. Ventriculomegaly, shortened femur length and pyelectasis were found in two cases. According to the literature, IUGR, pyelectasis and ventriculomegaly are common prenatal phenotypes of JBS. In addition, cardiac defects, trigonocephaly and shortened femur are also found. Our presentation of these cases provides more ultrasonic information for the prenatal diagnosis of this rare disease. Key Words: Ultrasound, Prenatal diagnosis, Jacobsen syndrome, Chromosomal abnormalities, Fetal malformation.

Immunological Evaluation of Patients Affected with Jacobsen Syndrome Reveals Profound Not Age-Related Lymphocyte Alterations.

PURPOSE: Jacobsen syndrome (JS) is a rare form of genetic disorder that was recently classified as a syndromic immunodeficiency. Available detailed immunological data from JS patients are limited. METHODS: Clinical and immunological presentation of twelve pediatric patients with JS by means of revision of clinical records, flow cytometry, real-time PCR, and lymphocyte functional testing were collected. RESULTS: Recurrent infections were registered in 6/12 patients (50%), while bleeding episodes in 2/12 (16.7%). White blood cell and absolute lymphocyte counts were reduced in 8/12 (66.7%) and 7/12 (58.3%) patients, respectively. Absolute numbers of CD3+ and CD4+ T cells were reduced in 8/12 (66.7%) and 7/12 (58.3%), respectively. Of note, recent thymic emigrants (RTE) were reduced in all tested patients (9/9), with T-cell receptor excision circle analysis (TRECs) showing a similar trend in 8/9 patients; naïve CD4+ T cells were low only in 5/11 patients (45.4%). Interestingly, B-cell counts, IgM memory B cells, and IgM serum levels were reduced in 10/12 (83.3%) patients. Natural killer (NK) cell counts were mostly normal but the percentages of CD16+CD56low/- cells were expanded in 7/7 patients tested. The observed immunological alterations did not correlate with patients' age. Finally, responses to proliferative stimuli were normal at presentation for all patients, although they may deteriorate over time. CONCLUSIONS: Our data suggest that patients affected with JS may display important numeric and maturational alterations in the T-, B-, and NK-cell compartments. These findings suggest that JS patients should be regularly monitored from an immunological point of view.

Immune Deficiency in Jacobsen Syndrome: Molecular and Phenotypic Characterization.

Jacobsen syndrome or JBS (OMIM #147791) is a contiguous gene syndrome caused by a deletion affecting the terminal q region of chromosome 11. The phenotype of patients with JBS is a specific syndromic phenotype predominately associated with hematological alterations. Complete and partial JBS are differentiated depending on which functional and causal genes are haploinsufficient in the patient. We describe the case of a 6-year-old Bulgarian boy in which it was possible to identify all of the major signs and symptoms listed by the Online Mendelian Inheritance in Man (OMIM) catalog using the Human Phenotype Ontology (HPO). Extensive blood and marrow tests revealed the existence of thrombocytopenia and leucopenia, specifically due to low levels of T and B cells and low levels of IgM. Genetic analysis using whole-genome single nucleotide polymorphisms (SNPs)/copy number variations (CNVs) microarray hybridization confirmed that the patient had the deletion arr[hg19]11q24.3q25(128,137,532-134,938,470)x1 in heterozygosis. This alteration was considered causal of partial JBS because the essential BSX and NRGN genes were not included, though 30 of the 96 HPO identifiers associated with this OMIM were identified in the patient. The deletion of the FLI-1, ETS1, JAM3 and THYN1 genes was considered to be directly associated with the immunodeficiency exhibited by the patient. Although immunodeficiency is widely accepted as a major sign of JBS, only constipation, bone marrow hypocellularity and recurrent respiratory infections have been included in the HPO as terms used to refer to the immunological defects in JBS. Exhaustive functional analysis and individual monitoring are required and should be mandatory for these patients.

Jacobsen syndrome and neonatal bleeding: report on two unrelated patients.

INTRODUCTION: In 1973, Petrea Jacobsen described the first patient showing dysmorphic features, developmental delay and congenital heart disease (atrial and ventricular septal defect) associated to a 11q deletion, inherited from the father. Since then, more than 200 patients have been reported, and the chromosomal critical region responsible for this contiguous gene disorder has been identified. PATIENTS' PRESENTATION: We report on two unrelated newborns observed in Italy affected by Jacobsen syndrome (JBS, also known as 11q23 deletion). Both patients presented prenatal and postnatal bleeding, growth and developmental delay, craniofacial dysmorphisms, multiple congenital anomalies, and pancytopenia of variable degree. Array comparative genomic hybridization (aCGH) identified a terminal deletion at 11q24.1-q25 of 12.5 Mb and 11 Mb, in Patient 1 and 2, respectively. Fluorescent in situ hybridization (FISH) analysis of the parents documented a de novo origin of the deletion for Patient 1; parents of Patient 2 refused further genetic investigations. CONCLUSIONS: Present newborns show the full phenotype of JBS including thrombocytopenia, according to their wide 11q deletion size. Bleeding was particularly severe in one of them, leading to a cerebral hemorrhage. Our report highlights the relevance of early diagnosis, genetic counselling and careful management and follow-up of JBS patients, which may avoid severe clinical consequences and lower the mortality risk. It may provide further insights and a better characterization of JBS, suggesting new elements of the genotype-phenotype correlations.

Loss of FEZ1, a gene deleted in Jacobsen syndrome, causes locomotion defects and early mortality by impairing motor neuron development.

FEZ1-mediated axonal transport plays important roles in central nervous system development but its involvement in the peripheral nervous system is not well-characterized. FEZ1 is deleted in Jacobsen syndrome (JS), an 11q terminal deletion developmental disorder. JS patients display impaired psychomotor skills, including gross and fine motor delay, suggesting that FEZ1 deletion may be responsible for these phenotypes, given its association with the development of motor-related circuits. Supporting this hypothesis, our data show that FEZ1 is selectively expressed in the rat brain and spinal cord. Its levels progressively increase over the developmental course of human motor neurons (MN) derived from embryonic stem cells. Deletion of FEZ1 strongly impaired axon and dendrite development, and significantly delayed the transport of synaptic proteins into developing neurites. Concurring with these observations, Drosophila unc-76 mutants showed severe locomotion impairments, accompanied by a strong reduction of synaptic boutons at neuromuscular junctions. These abnormalities were ameliorated by pharmacological activation of UNC-51/ATG1, a FEZ1-activating kinase, with rapamycin and metformin. Collectively, the results highlight a role for FEZ1 in MN development and implicate its deletion as an underlying cause of motor impairments in JS patients.