Skip to main content
SpringerLink
Log in

Klinefelter syndrome: cardiovascular abnormalities and metabolic disorders

  • Short Review
  • Published:
Journal of Endocrinological Investigation Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  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):615–624

    Article  CAS  Google Scholar 

  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

    CAS  Google Scholar 

  3. Bojesen A, Juul S, Gravholt CH (2003) Prenatal and postnatal prevalence of Klinefelter syndrome: a national registry study. J Clin Endocrinol Metab 88(2):622–626. doi:10.1210/jc.2002-021491

    Article  CAS  PubMed  Google Scholar 

  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):1254–1260

    Article  CAS  PubMed  Google Scholar 

  5. Bojesen A, Stochholm K, Juul S, Gravholt CH (2011) Socioeconomic trajectories affect mortality in Klinefelter syndrome. J Clin Endocrinol Metab 96(7):2098–2104. doi:10.1210/jc.2011-0367

    Article  CAS  PubMed  Google Scholar 

  6. Bojesen A, Juul S, Birkerbaek N, Gravholt CH (2004) Increased mortality in Klinefelter syndrome. J Clin Endocrinol Metab 89(8):3830–3834

    Article  CAS  PubMed  Google Scholar 

  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):6516–6522

    Article  CAS  PubMed  Google Scholar 

  8. Bojesen A, Gravholt CH (2011) Morbidity and mortality in Klinefelter’s syndrome (47,XXY). Acta Paediatr 100(6):807–813. doi:10.1111/j.1651-2227.2011.02274.x

    Article  PubMed  Google Scholar 

  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):177–88

    Article  CAS  PubMed  Google Scholar 

  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):330–336

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  PubMed  Google Scholar 

  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):1148–1150

    Article  CAS  PubMed  Google Scholar 

  13. Fricke GR, Mattern HJ, Schweikert HU (1981) Mitral valve prolapse in Klinefelter syndrome. The Lancet 2(8260–61):1414

    Article  CAS  Google Scholar 

  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):867–870

    CAS  PubMed  Google Scholar 

  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):391–395

    CAS  PubMed  Google Scholar 

  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.520522

    PubMed  Google Scholar 

  17. Agarwal S, Dekam MJ (2011) Multiple cardiac anomalies in an elderly man with Klinefelter’s syndrome. Singapore Med J 52(1):e15–e17

    CAS  PubMed  Google Scholar 

  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):1371–1374

    Article  PubMed  Google Scholar 

  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):969–72

    Article  PubMed  Google Scholar 

  20. Okayama S, Uemura S, Saito Y (2013) Hypertrophic cardiomyopathy and mesenteric venous thrombosis in a patient with Klinefelter’ syndrome. Int J Cardiol 166(3):e50–e52. doi:10.1016/j.ijcard.2013.01.177

    Article  PubMed  Google Scholar 

  21. Karagöz A, Dikbaş O, Teker E, Vural A, Günaydın ZY, Bektaş O (2015) Sinus node dysfunction requiring permanent pacemaker implantation in a young adult with Klinefelter syndrome. Am J Case Rep 16:136–139. doi:10.12659/AJCR.893065

    Article  PubMed  PubMed Central  Google Scholar 

  22. Foresta C, Caretta N, Palego P, Ferlin A, Zuccarello D, Lenzi A, Selice R (2012) Reduced artery diameters in Klinefelter syndrome. Int J Androl 35(5):720–725. doi:10.1111/j.1365-2605.2012.01269.x

    Article  CAS  PubMed  Google Scholar 

  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):95–98

    Article  PubMed  Google Scholar 

  24. Igawa K, Nishioka K (2003) Leg ulcer in Klinefelter’s syndrome. J Eur Acad Dermatol Venereol 17(1):62–64

    Article  CAS  PubMed  Google Scholar 

  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

    Article  PubMed  Google Scholar 

  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):623–626

    Article  PubMed  Google Scholar 

  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):240–242

    Article  CAS  PubMed  Google Scholar 

  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):369–371

    Article  PubMed  Google Scholar 

  29. Gattringer C, Scheurecker C, Höpfl R, Müller H (2010) Association between venous leg ulcers and sex chromosome anomalies in men. Acta Derm Venereol 90(6):612–615. doi:10.2340/00015555-0949

    Article  PubMed  Google Scholar 

  30. Shanmugam VK, Tsagaris KC, Attinger CE (2012) Leg ulcers associated with Klinefelter’s syndrome: a case report and review of the literature. Int Wound J 9(1):104–107. doi:10.1111/j.1742-481X.2011.00846.x

    Article  PubMed  Google Scholar 

  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):341–344

    Article  CAS  PubMed  Google Scholar 

  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):876–881

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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)

    Article  CAS  PubMed  Google Scholar 

  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

    PubMed  PubMed Central  Google Scholar 

  37. Chang S, Skakkebæk A, Gravholt CH (2015) Klinefelter Syndrome and medical treatment: hypogonadism and beyond. Hormones (Athens) 14(4):531–548. doi:10.14310/horm.2002.1622

    Google Scholar 

  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

    CAS  PubMed  Google Scholar 

  39. Bardsley MZ, Falkner B, Kowal K, Ross JL (2011) Insulin resistance and metabolic syndrome in prepubertal boys with Klinefelter syndrome. Acta Paediatr 100(6):866–870. doi:10.1111/j.1651-2227.2011.02161.x

    Article  PubMed  PubMed Central  Google Scholar 

  40. East BW, Boddy K, Price WH (1976) Total body potassium content in males with X and Y chromosome abnormalities. Clin Endocrinol 5(1):43–51

    Article  CAS  Google Scholar 

  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):30–34

    Article  CAS  PubMed  Google Scholar 

  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):1591–1598

    Article  PubMed  Google Scholar 

  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):1062–1073

    Article  CAS  PubMed  Google Scholar 

  44. Ishikawa T, Yamaguchi K, Kondo Y, Takenaka A, Fujisawa M (2008) Metabolic syndrome in men with Klinefelter’s syndrome. Urology 71(6):1109–1113. doi:10.1016/j.urology.2008.01.051

    Article  PubMed  Google Scholar 

  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):485–491

    Article  CAS  PubMed  Google Scholar 

  46. Corona G, Mannucci E, Forti G, Maggi M (2009) Hypogonadism, ED, metabolic syndrome and obesity: a pathological link supporting cardiovascular diseases. Int J Androl 32(6):587–598. doi:10.1111/j.1365-2605.2008.00951.x

    Article  CAS  PubMed  Google Scholar 

  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):1288–1299

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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):4254–4259

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  Google Scholar 

Download references

Acknowledgements

On behalf of the Klinefelter ItaliaN Group (KING). Coordinators: Giancarlo Balercia (Ancona), Marco Bonomi (Milano), Aldo E. Calogero (Catania), Giovanni Corona (Bologna), Andrea Fabbri (Roma), Alberto Ferlin (Padova), Felice Francavilla (L’Aquila), Vito Giagulli (Conversano, Bari), Fabio Lanfranco (Torino), Mario Maggi (Firenze), Daniela Pasquali (Napoli), Rosario Pivonello (Napoli), Alessandro Pizzocaro (Milano), Antonio Radicioni (Roma), Vincenzo Rochira (Modena), Linda Vignozzi (Firenze); Members: Giacomo Accardo (Napoli), Biagio Cangiano (Milano), Rosita A. Condorelli (Catania), Giuliana Cordeschi (L’Aquila), Settimio D’Andrea (L’Aquila), Antonella Di Mambro (Padova), Daniela Esposito (Napoli), Carlo Foresta (Padova), Sandro Francavilla (L’Aquila), Mariano Galdiero (Napoli), Andrea Garolla (Padova), Lara Giovannini (Ancona), Antonio R.M. Granata (Modena), Sandro La Vignera (Catania), Giovanna Motta (Torino), Luciano Negri (Milano), Fiore Pelliccione (L’Aquila), Luca Persani (Milano), Ciro Salzano (Napoli), Daniele Santi (Modena), Riccardo Selice (Padova), Manuela Simoni (Modena), Carla Tatone (L’Aquila), Giacomo Tirabassi (Ancona), Alberto Stefano Tresoldi (Milano), Enzo Vicari (Catania).

Author information

Authors and Affiliations

  1. Department of Clinical and Experimental Medicine, University of Catania, Policlinico “G. Rodolico”, via S. Sofia 78, 95123, Catania, Italy

    A. E. Calogero & L. M. Mongioì

  2. Department of Endocrinology and Metabolic Diseases, University of Bari, Bari, Italy

    V. A. Giagulli

  3. Outpatient Clinic for Endocrinology and Metabolic Diseases, Conversano Hospital, Conversano, Italy

    V. Triggiani

  4. Department of Experimental Medicine, La Sapienza University of Rome, Rome, Italy

    A. F. Radicioni

  5. Department of Systems Medicine, Tor Vergata University of Rome, Rome, Italy

    E. A. Jannini

  6. Department of Medical, Surgical, Neurological, Metabolic and Aging Sciences, Second University of Naples, Naples, Italy

    D. Pasquali

Authors
  1. A. E. Calogero
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. V. A. Giagulli
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. L. M. Mongioì
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. V. Triggiani
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. A. F. Radicioni
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. E. A. Jannini
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. D. Pasquali
    View author publications

    You can also search for this author in PubMed Google Scholar

Consortia

On behalf of the Klinefelter ItaliaN Group (KING)

  • Giancarlo Balercia
  • , Marco Bonomi
  • , Aldo E. Calogero
  • , Giovanni Corona
  • , Andrea Fabbri
  • , Alberto Ferlin
  • , Felice Francavilla
  • , Vito Giagulli
  • , Fabio Lanfranco
  • , Mario Maggi
  • , Daniela Pasquali
  • , Rosario Pivonello
  • , Alessandro Pizzocaro
  • , Antonio Radicioni
  • , Vincenzo Rochira
  • , Linda Vignozzi
  • , Giacomo Accardo
  • , Biagio Cangiano
  • , Rosita A. Condorelli
  • , Giuliana Cordeschi
  • , Settimio D’Andrea
  • , Antonella Di Mambro
  • , Daniela Esposito
  • , Carlo Foresta
  • , Sandro Francavilla
  • , Mariano Galdiero
  • , Andrea Garolla
  • , Lara Giovannini
  • , Antonio R. M. Granata
  • , Sandro La Vignera
  • , Giovanna Motta
  • , Luciano Negri
  • , Fiore Pelliccione
  • , Luca Persani
  • , Ciro Salzano
  • , Daniele Santi
  • , Riccardo Selice
  • , Manuela Simoni
  • , Carla Tatone
  • , Giacomo Tirabassi
  • , Alberto Stefano Tresoldi
  •  & Enzo Vicari

Corresponding author

Correspondence to A. E. Calogero.

Ethics declarations

Funding

This study did not receive specific funding.

Conflict of interest

AEC, LMM, VT and DP declare that they have no conflict of interest. VAG has been a paid speaker and/or consultant for Bayer. EAJ is or has been a paid speaker and/or consultant for Bayer, Bracco, Gsk, IBSA, Menarini and Pfizer.

Ethical approval

This article does not contain any studies with human participants or animals performed by the authors. Informed consent/formal consent is not required.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Calogero, A.E., Giagulli, V.A., Mongioì, L.M. et al. Klinefelter syndrome: cardiovascular abnormalities and metabolic disorders. J Endocrinol Invest 40, 705–712 (2017). https://doi.org/10.1007/s40618-017-0619-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40618-017-0619-9

Keywords

Search

Navigation