DOI: 10.1530/EJE-15-1025 Printed in Great Britain Published by Bioscientifica Ltd. European Journal of Endocrinology www.eje-online.org © 2016 European Society of Endocrinology MANAGEMENT OF ENDOCRINE DISEASE Klinefelter syndrome, cardiovascular system, and thromboembolic disease: review of literature and clinical perspectives Andrea Salzano 1 , Michele Arcopinto 2 , Alberto M Marra 3 , Emanuele Bobbio 1 , Daniela Esposito 4 , Giacomo Accardo 4 , Francesco Giallauria 1 , Eduardo Bossone 5 , Carlo Vigorito 1 , Andrea Lenzi 6 , Daniela Pasquali 4 , Andrea M Isidori 6 and Antonio Cittadini 1 1 Department of Translational Medical Sciences, University “Federico II”, Naples, Italy, 2 Department of Cardiac Surgery, IRCCS Policlinico San Donato, Milan, Italy, 3 IRCSS SDN, Via E. Gianturco 113, Naples, Italy, 4 Department of Cardiothoracic and Respiratory Science, Endocrinology Unit, Second University of Naples, Italy, 5 Department of Cardiology and Cardiac Surgery, University Hospital “Scuola Medica Salernitana”, Salerno, Italy and 6 Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy Abstract Klinefelter syndrome (KS) is the most frequently occurring sex chromosomal aberration in males, with an incidence of about 1 in 500 – 700 newborns. Data acquired from large registry-based studies revealed an increase in mortality rates among KS patients when compared with mortality rates among the general population. Among all causes of death, metabolic, cardiovascular, and hemostatic complication seem to play a pivotal role. KS is associated, as are other chromosomal pathologies and genetic diseases, with cardiac congenital anomalies that contribute to the increase in mortality. The aim of the current study was to systematically review the relationships between KS and the cardiovascular system and hemostatic balance. In summary , patients with KS display an increased cardiovascular risk profle, characterized by increased prevalence of metabolic abnormalities including Diabetes mellitus (DM), dyslipidemia, and alterations in biomarkers of cardiovascular disease. KS does not, however, appear to be associated with arterial hypertension. Moreover, KS patients are characterized by subclinical abnormalities in left ventricular (LV) systolic and diastolic function and endothelial function, which, when associated with chronotropic incompetence may led to reduced cardiopulmonary performance. KS patients appear to be at a higher risk for cardiovascular disease, attributing to an increased risk of thromboembolic events with a high prevalence of recurrent venous ulcers, venous insuffciency, recurrent venous and arterial thromboembolism with higher risk of deep venous thrombosis or pulmonary embolism. It appears that cardiovascular involvement in KS is mainly due to chromosomal abnormalities rather than solely on low serum testosterone levels. On the basis of evidence acquisition and authors’ own experience, a fowchart addressing the management of cardiovascular function and prognosis of KS patients has been developed for clinical use. 175:1 R27–R40 Andrea Salzano and others KS cardiovascular system, and thromboembolic disease Correspondence should be addressed to Antonio Cittadini Email antonio.cittadini@unina.it European Journal of Endocrinology (2016) 175, R27–R40 Review Introduction Klinefelter syndrome (KS) is the most common abnormality of sex chromosomes (47, XXY or a mosaic karyotype) and is characterized by hypergonadotropic hypogonadism (1). Data indicate the incidence of KS to be as high as 1/660 of newborns (2, 3). Despite its frst mention being 70 years ago (1), little data are available with regard to the morbidity and mortality of KS. Data from recent large registry-based studies (4, 5, 6, 7, 8) indicated an increase in mortality in KS patients when compared with the general population. Interestingly, mortality was specifcally increased by