Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Journal of Endocrinological Investigation
Published in: Journal of Endocrinological Investigation 7/2017

01-07-2017 | Short Review

Klinefelter syndrome: cardiovascular abnormalities and metabolic disorders

Authors: A. E. Calogero, V. A. Giagulli, L. M. Mongioì, V. Triggiani, A. F. Radicioni, E. A. Jannini, D. Pasquali, On behalf of the Klinefelter ItaliaN Group (KING)

Published in: Journal of Endocrinological Investigation | Issue 7/2017

Login to get access

Abstract

Klinefelter syndrome (KS) is one of the most common genetic causes of male infertility. This condition is associated with much comorbidity and with a lower life expectancy. The aim of this review is to explore more in depth cardiovascular and metabolic disorders associated to KS. KS patients have an increased risk of cerebrovascular disease (standardized mortality ratio, SMR, 2.2; 95% confidence interval, CI, 1.6–3.0), but it is not clear whether the cause of the death is of thrombotic or hemorrhagic nature. Cardiovascular congenital anomalies (SMR, 7.3; 95% CI, 2.4–17.1) and the development of thrombosis or leg ulcers (SMR, 7.9; 95% CI, 2.9–17.2) are also more frequent in these subjects. Moreover, cardiovascular abnormalities may be at least partially reversed by testosterone replacement therapy (TRT). KS patients have also an increased probability of endocrine and/or metabolic disease, especially obesity, metabolic syndrome and type 2 diabetes mellitus. The effects of TRT on these abnormalities are not entirely clear.
Literature
1.
Klinefelter HF Jr, Reifenstein EC Jr, Albright F (1942) Syndrome characterized by gynecomastia aspermatogenesis without a-Leydigism and increased excretion of follicle-stimulating hormone. J Clin Endocrol 2(11):615–624CrossRef
2.
Forti G, Corona G, Vignozzi L, Krausz C, Maggi M (2010) Klinefelter’s syndrome: a clinical and therapeutical update. Sex Dev Gene Mol Biol Evol Endocrinol Embryol Pathol Sex Determ Differ 4(4–5):249–258. doi:10.​1159/​000316604
3.
4.
Bojesen A, Juul S, Birkebaek N, Gravholt CH (2006) Morbidity in Klinefelter’s syndrome: a Danish register study based on hospital discharge diagnoses. J Clin Endocrinol Metab 91(4):1254–1260CrossRefPubMed
5.
6.
Bojesen A, Juul S, Birkerbaek N, Gravholt CH (2004) Increased mortality in Klinefelter syndrome. J Clin Endocrinol Metab 89(8):3830–3834CrossRefPubMed
7.
Swerdlow AJ, Higgin CD, Schomaker MJ, Wright AF, Jacobs PA (2005) Mortality in patients with Klinefelter’s syndrome in Britain: a cohort study. J Clin Endocrinol Metab 90(12):6516–6522CrossRefPubMed
8.
9.
Swerdlow AJ, Hermon C, Jacobs PA, Alberman E, Beral V, Daker M, Fordyce A, Youings S (2001) Mortality and cancer incidence in persons with numerical sex chromosome abnormalities: a cohort study. Ann Hum Genet 65(Pt 2):177–88CrossRefPubMed
10.
Price WH, Clayton JF, Wilson J, Collyer S, De Mey R (1985) Causes of death in X chromatin positive males (Klinefelter’s syndrome). J Epidemiol Community Health 39(4):330–336CrossRefPubMedPubMedCentral
11.
Pasquali D, Arcopinto M, Renzullo A, Rotondi M, Accardo G, Salzano A, Esposito D, Saldamarco L, Isidori AM, Marra AM, Ruvolo A, Napoli R, Bossone E, Lenzi A, Baliga RR, Saccà L, Cittadini A (2013) Cardiovascular abnormalities in Klinefelter syndrome. Int J Cardiol 168(2):754–759. doi:10.​1016/​j.​ijcard.​2012.​09.​215 CrossRefPubMed
12.
Kominato Y, Fujikura T, Matsui K, Hata N, Takizawa H (2000) Acute cerebellar hemorrhage in a patient with Klinefelter syndrome: XXY karyotype obtained postmortem from cells from pericardial fluid. J Forensic Sci 45(5):1148–1150CrossRefPubMed
13.
Fricke GR, Mattern HJ, Schweikert HU (1981) Mitral valve prolapse in Klinefelter syndrome. The Lancet 2(8260–61):1414CrossRef
14.
Katsumata T, Tomizawa Y, Okoshi T, Ego Y, Iguchi N, Saigusa H, Nakagawa M, Kobayashi H, Kato T, Takahashi S (1991) A case of Klinefelter’s syndrome with acute mitral regurgitation caused by idiopathic chordal rupture. Kyobu Geka 44(10):867–870PubMed
15.
Fujikane M, Katayama S, Yokota N, Hirata K, Ichimaru Y (1994) Klinefelter syndrome accompanied by hypoplasia of the bilateral internal carotid arteries—a case report. Rinsho Shinkeigaku 34(4):391–395PubMed
16.
Ahmed S, Hafeez S, Ali N, Ahmed T (2009) Hypertrophic cardiomyopathy in a patient of Klinefelter syndrome—a rare association. J Coll Physicians Surg Pak 19(8):520–522. doi:08.2009/JCPSP.520522PubMed
17.
Agarwal S, Dekam MJ (2011) Multiple cardiac anomalies in an elderly man with Klinefelter’s syndrome. Singapore Med J 52(1):e15–e17PubMed
18.
Shen Z, Zou CC, Shang SQ, Jiang KW (2012) Down-Klinefelter syndrome (48,XXY,+21) in a child with congenital heart disease: case report and literature review. Intern Med 51(11):1371–1374CrossRefPubMed
19.
Ueki Y, Izawa A, Ebisawa S, Motoki H, Miyashita Y, Tomita T, Koyama J, Takano T, Amano J, Ikeda U (2014) Infective endocarditis associated with mitral valve prolapse in a patient with Klinefelter syndrome. Intern Med 53(9):969–72CrossRefPubMed
20.
21.
22.
23.
Lapecorella M, Marino R, De Pergola G, Scaraggi FA, Speciale V, De Mitrio V (2003) Severe venous thromboembolism in a young man with Klinefelter’s syndrome and heterozygosis for both G20210A prothrombin and factor V Leiden mutations. Blood Coagul Fibrinolysis 14(1):95–98CrossRefPubMed
24.
Igawa K, Nishioka K (2003) Leg ulcer in Klinefelter’s syndrome. J Eur Acad Dermatol Venereol 17(1):62–64CrossRefPubMed
25.
Goto Y, Uhara H, Murata H, Koga H, Kosho T, Yamazaki M, Takata M, Okuyama R (2011) Leg ulcers associated with positive lupus anticoagulant in two cases of Klinefelter’s syndrome. Acta Derm Venereol 91(1):90–91. doi:10.​2340/​00015555-0957 CrossRefPubMed
26.
Kasten R, Pfirrmann G, Voigtländer V (2005) Klinefelter’s syndrome associated with mixed connective tissue disease (Sharp’s syndrome) and thrombophilia with post-thrombotic syndrome. J Dtsch Dermatol Ges 3(8):623–626CrossRefPubMed
27.
Dissemond J, Knab J, Lehnen M, Goos M (2005) Increased activity of factor VIII coagulant associated with venous ulcer in a patient with Klinefelter’s syndrome. J Eur Acad Dermatol Venereol 19(2):240–242CrossRefPubMed
28.
Ozbek M, Oztürk MA, Ureten K, Ceneli O, Erdogan M, Haznedaroglu IC (2008) Severe arterial thrombophilia associated with a homozygous MTHFR gene mutation (A1298C) in a young man with Klinefelter syndrome. Clin Appl Thromb Hemost 14(3):369–371CrossRefPubMed
29.
30.
31.
Zollner TM, Veraart JC, Wolter M, Hesse S, Villemur B, Wenke A, Werner RJ, Boehncke WH, Jost SS, Scharrer I, Kaufmann R (1997) Leg ulcers in Klinefelter’s syndrome—further evidence for an involvement of plasminogen activator inhibitor-1. Br J Dermatol 136(3):341–344CrossRefPubMed
32.
Di Minno MN, Esposito D, Di Minno A, Accardo G, Lupoli G, Cittadini A, Giugliano D, Pasquali D (2015) Increased platelet reactivity in Klinefelter men: something new to consider. Andrology 3(5):876–881CrossRefPubMed
33.
Di Mambro A, Ferlin A, De Toni L, Selice R, Caretta N, Foresta C (2010) Endothelial progenitor cells as a new cardiovascular risk factor in Klinefelter’s syndrome. Mol Hum Reprod 16(6):411–417. doi:10.​1093/​molehr/​gaq015 CrossRefPubMed
34.
Radicioni AF, Ferlin A, Balercia G, Pasquali D, Vignozzi L, Maggi M, Foresta C, Lenzi A (2010) Consensus statement on diagnosis and clinical management of Klinefelter syndrome. J Endocrinol Invest 33(11):839–850. doi:10.​1007/​BF03350351 CrossRefPubMed
35.
Radicioni AF, De Marco E, Gianfrilli D, Granato S, Gandini L, Isidori AM, Lenzi A (2010) Strategies and advantages of early diagnosis in Klinefelter’s syndrome. Mol Hum Reprod 16(6):434–440. doi:10.​1093/​molehr/​gaq027 (Epub 2010 Apr 14) CrossRefPubMed
36.
Bonomi M, Rochira V, Pasquali D, Balercia G, Jannini EA, Ferlin A, Klinefelter ItaliaN Group (KING) (2016) Klinefelter syndrome (KS): genetics, clinical phenotype and hypogonadism. J Endocrinol Invest Sep 19 [Epub ahead of print] Review. doi:10.​1007/​s40618-016-0541-6 PubMedPubMedCentral
37.
38.
Condorelli RA, Calogero AE, La Vignera S (2013) Different profile of endothelial cell apoptosis in patients with Klinefelter’s syndrome. J Endocrinol Invest 36(2):84–91. doi:10.​3275/​8287 PubMed
39.
40.
East BW, Boddy K, Price WH (1976) Total body potassium content in males with X and Y chromosome abnormalities. Clin Endocrinol 5(1):43–51CrossRef
41.
Aksglaede L, Molgaard C, Skakkebaek NE, Juul A (2008) Normal bone mineral content but unfavourable muscle/fat ratio in Klinefelter syndrome. Arch Dis Child 93(1):30–34CrossRefPubMed
42.
Bojesen A, Kristensen K, Birkebaek NH, Fedder J, Mosekilde L, Bennett P, Laurberg P, Frystyk J, Flyvbjerg A, Christiansen JS, Gravholt CH (2006) The metabolic syndrome is frequent in Klinefelter’s syndrome and is associated with abdominal obesity and hypogonadism. Diabetes Care 29(7):1591–1598CrossRefPubMed
43.
Nielsen J, Johansen K, Yde H (1969) Frequency of diabetes mellitus in patients with Klinefelter’s syndrome of different chromosome constitutions and the XYY syndrome. Plasma insulin and growth hormone level after a glucose load. J Clin Endocrinol Metab 29(8):1062–1073CrossRefPubMed
44.
45.
Tsai EC, Boyko EJ, Leonetti DL, Fujimoto WY (2000) Low serum testosterone level as a predictor of increased visceral fat in Japanese-American men. Int J Obes Relat Metab Disord 24(4):485–491CrossRefPubMed
46.
47.
Ding EL, Song Y, Malik VS, Liu S (2006) Sex differences of endogenous sex hormones and risk of type 2 diabetes: a systematic review and meta-analysis. JAMA 295(11):1288–1299CrossRefPubMed
48.
Corona G, Rastrelli G, Monami M, Saad F, Luconi M, Lucchese M, Facchiano E, Sforza A, Forti G, Mannucci E, Maggi M (2013) Body weight loss reverts obesity-associated hypogonadotropic hypogonadism: a systematic review and meta-analysis. Eur J Endocrinol 168(6):829–843. doi:10.​1530/​EJE-12-0955 CrossRefPubMed
49.
Yialamas MA, Dwyer AA, Hanley E, Lee H, Pitteloud N, Hayes FJ (2007) Acute sex steroid withdrawal reduces insulin sensitivity in healthy men with idiopathic hypogonadotropic hypogonadism. J Clin Endocrinol Metab 92(11):4254–4259CrossRefPubMed
50.
Lapauw B, Ouwens M, ‘t Hart LM, Wuyts B, Holst JJ, T’Sjoen G, Kaufman JM, Ruige JB (2010) Sex steroids affect triglyceride handling, glucose-dependent insulinotropic polypeptide, and insulin sensitivity: a 1-week randomized clinical trial in healthy young men. Diabetes Care 33(8):1831–1833. doi:10.​2337/​dc10-0515 CrossRefPubMedPubMedCentral
51.
Corona G, Giagulli VA, Maseroli E, Vignozzi L, Aversa A, Zitzmann M, Saad F, Mannucci E, Maggi M (2016) Therapy of endocrine: testosterone supplementation and body composition: results from a meta-analysis study. Eur J Endocrinol 174(3):R99–R116. doi:10.​1530/​EJE-15-0262 CrossRefPubMed
52.
Corona G, Giagulli VA, Maseroli E, Vignozzi L, Aversa A, Zitzmann M, Saad F, Mannucci E, Maggi M (2016) Testosterone supplementation and body composition: results from a meta-analysis of observational studies. J Endocrinol Invest 9(9):967–981. doi:10.​1007/​s40618-016-0480-2 CrossRef
53.
Giagulli VA, Carbone MD, Ramunni MI, Licchelli B, De Pergola G, Sabbà C, Guastamacchia E, Triggiani V (2015) Adding liraglutide to lifestyle changes, metformin and testosterone therapy boosts erectile function in diabetic obese men with overt hypogonadism. Andrology 3(6):1094–1103. doi:10.​1111/​andr.​12099.CrossRefPubMed
54.
Zitzmann M, Depenbusch M, Gromoll J, Nieschlag E (2004) X-chromosome inactivation patterns and androgen receptor functionality influence phenotype and social characteristics as well as pharmacogenetics of testosterone therapy in Klinefelter patients. J Clin Endocrinol Metab 89(12):6208–6217. doi:10.​1210/​jc.​2004-1424 CrossRefPubMed
55.
Zitzmann M, Bongers R, Werler S, Bogdanova N, Wistuba J, Kliesch S, Gromoll J, Tüttelmann F (2015) Gene expression patterns in relation to the clinical phenotype in Klinefelter syndrome. J Clin Endocrinol Metab 100(3):E518–E523. doi:10.​1210/​jc.​2014-2780 CrossRefPubMed
56.
Rotondi M, Coperchini F, Renzullo A, Accardo G, Esposito D, Groppelli G, Magri F, Cittadini A, Isidori AM, Chiovato L, Pasquali D (2014) High circulating levels of CCL2 in patients with Klinefelter’s syndrome. Clin Endocrinol (Oxf) 80(3):465–7. doi:10.​1111/​cen.​12245.​Epub2013Jun11 CrossRef
Metadata
Title
Klinefelter syndrome: cardiovascular abnormalities and metabolic disorders
Authors
A. E. Calogero
V. A. Giagulli
L. M. Mongioì
V. Triggiani
A. F. Radicioni
E. A. Jannini
D. Pasquali
On behalf of the Klinefelter ItaliaN Group (KING)
Publication date
01-07-2017
Publisher
Springer International Publishing
Published in
Journal of Endocrinological Investigation / Issue 7/2017
Electronic ISSN: 1720-8386
DOI
https://doi.org/10.1007/s40618-017-0619-9

Other articles of this Issue 7/2017

Journal of Endocrinological Investigation 7/2017 Go to the issue

Original Article

Evaluation of serum hepcidin and iron levels in patients with PCOS: a case-control study

Original Article

Correlation between pre-ramadan glycemic control and subsequent glucose fluctuation during fasting in adolescents with Type 1 diabetes

Endocrinology & Art

A likely cranial osteodystrophy (Paget’s disease of bone) in a Precolumbian, Mesoamerican stone sculpture

Original Article

Antitumor activity of interferon-β1a in hormone refractory prostate cancer with neuroendocrine differentiation

Original Article

Effect of metformin and oral contraceptives on polycystic ovary syndrome and IVF cycles

Review

Challenges in assessing personality of individuals with Gender Dysphoria with the SWAP-200
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits