First baseline data of the Klinefelter ItaliaN Group (KING) cohort: clinical features of adult with Klinefelter syndrome in Italy.

Follicle Stimulating Hormone / therapeutic use Humans Hypogonadism / drug therapy Klinefelter Syndrome / complications Male Metabolic Syndrome / complications Testis Testosterone / therapeutic use

BMI FSH Klinefelter syndrome LH MetS Metabolic syndrome Testis Testosterone

Journal

Journal of endocrinological investigation

ISSN: 1720-8386

Titre abrégé: J Endocrinol Invest

Pays: Italy

ID NLM: 7806594

Informations de publication

Date de publication:
Sep 2022

Historique:

received: 17 09 2021

accepted: 29 04 2022

pubmed: 25 5 2022

medline: 11 8 2022

entrez: 24 5 2022

Statut: ppublish

Résumé

Klinefelter syndrome (KS) is frustratingly under-diagnosed. KS have a broad spectrum of clinical features, making it difficult to identify. OBJECTIVE: We describe KS clinical presentation in a large Italian cohort. This is the first observational cohort study within a national network, the Klinefelter ItaliaN Group (KING). Primary outcomes were to describe the basic clinical features and the actual phenotype of KS in Italy. Secondary outcomes were to determine age at diagnosis and geographical distribution. We performed a basic phenotyping and evaluation of the hormonal values of 609 adult KS patients. Mean age at diagnosis was 37.4 ± 13.4 years. The overall mean testicular size was 3 ml, and 2.5 ml in both testes in untreated KS group. BMI was 26.6 ± 5.8 kg/m These data are the results of the only national database available that collects the clinical and hormonal data of the KS patients, currently referred at the KING centers. In Italy the typical KS patient is overweight, with small testes, and elevated LH and FSH. Only 25.5% of them are diagnosed with MetS. Early detection and timely treatment are mandatory.

Sections du résumé

BACKGROUND BACKGROUND

DESIGN METHODS

This is the first observational cohort study within a national network, the Klinefelter ItaliaN Group (KING). Primary outcomes were to describe the basic clinical features and the actual phenotype of KS in Italy. Secondary outcomes were to determine age at diagnosis and geographical distribution.

METHODS METHODS

We performed a basic phenotyping and evaluation of the hormonal values of 609 adult KS patients.

RESULTS RESULTS

Mean age at diagnosis was 37.4 ± 13.4 years. The overall mean testicular size was 3 ml, and 2.5 ml in both testes in untreated KS group. BMI was 26.6 ± 5.8 kg/m

CONCLUSIONS CONCLUSIONS

These data are the results of the only national database available that collects the clinical and hormonal data of the KS patients, currently referred at the KING centers. In Italy the typical KS patient is overweight, with small testes, and elevated LH and FSH. Only 25.5% of them are diagnosed with MetS. Early detection and timely treatment are mandatory.

Identifiants

DOI: 10.1007/s40618-022-01816-4 PMID: 35608733 PMC: PMC9360143

pubmed: 35608733

doi: 10.1007/s40618-022-01816-4

pii: 10.1007/s40618-022-01816-4

pmc: PMC9360143

doi:

Substances chimiques

Testosterone 3XMK78S47O

Follicle Stimulating Hormone 9002-68-0

Types de publication

Journal Article Observational Study

Langues

eng

Sous-ensembles de citation

Pagination

1769-1776

Subventions

Organisme : Istituto Auxologico Italiano

ID : 05C622_2016

Organisme : Università degli Studi di Torino

ID : ex-60% 2020

Investigateurs

D Pasquali (D)

A Ferlin (A)

L Vignozzi (L)

G Corona (G)

F Lanfranco (F)

V Rochira (V)

A E Calogero (AE)

M Bonomi (M)

R Pivonello (R)

G Balercia (G)

A Pizzocaro (A)

V A Giagulli (VA)

P Salacone (P)

A Aversa (A)

G Accardo (G)

M Maggi (M)

A Lenzi (A)

A Isidori (A)

C Foresta (C)

E A Jannini (EA)

A Garolla (A)

Informations de copyright

Références

Klinefelter HF, Reifenstein EC, Albright F (1942) Syndrome characterized by gynecomastia, aspermatogenesis without A-Leydigism, and increased excretion of follicle stimulating hormone. J Clin Endocrinol Metab 2(11):615–627

doi: 10.1210/jcem-2-11-615

Nieschlag E, Ferlin A, Gravholt CH, Gromoll J, Köhler B, Lejeune H, Rogol AD, Wistuba J (2016) The Klinefelter syndrome: current management and research challenges. Andrology 4(3):545–549

doi: 10.1111/andr.12208

Groth KA, Skakkebæk A, Høst C, Gravholt CH, Bojesen A (2013) Clinical review: Klinefelter syndrome–a clinical update. J Clin Endocrinol Metab 98(1):20–30

doi: 10.1210/jc.2012-2382

Bonomi M, Rochira V, Pasquali D, Balercia G, Jannini EA, Ferlin A Klinefelter ItaliaN Group (KING) (2017) Klinefelter syndrome (KS): genetics, clinical phenotype and hypogonadism. J Endocrinol Invest 40(2):123–134

doi: 10.1007/s40618-016-0541-6

Kanakis GA, Nordkap L, Bang AK, Calogero AE, Bártfai G, Corona G, Forti G, Toppari J, Goulis DG, Jørgensen N (2019) EAA clinical practice guidelines—gynecomastia evaluation and management. Andrology 7:778–793

doi: 10.1111/andr.12636

Giagulli VA, Campone B, Castellana M, Salzano C, Fisher AD, de Angelis C, Pivonello R, Colao A, Pasquali D, Maggi M, Triggiani V, On Behalf Of The Klinefelter ItaliaN Group KING (2019) Neuropsychiatric aspects in men with Klinefelter syndrome. Endocr Metab Immune Disord Drug Targets 19(2):109–115

doi: 10.2174/1871530318666180703160250

Berglund A, Viuff MH, Skakkebæk A, Chang S, Stochholm K, Gravholt CH (2019) Changes in the cohort composition of Turner syndrome and severe non-diagnosis of Klinefelter, 47, XXX and 47, XYY syndrome: a nationwide cohort study. Orphanet J Rare Dis 14:16. https://doi.org/10.1186/s13023-018-0976-2

doi: 10.1186/s13023-018-0976-2 pubmed: 30642344 pmcid: 6332849

Corona G, Pizzocaro A, Lanfranco F, Garolla A, Pelliccione F, Vignozzi L, Ferlin A, Foresta C, Jannini EA, Maggi M, Lenzi A, Pasquali D, Francavilla S; Klinefelter ItaliaN Group (KING) (2017) Sperm recovery and ICSI outcomes in Klinefelter syndrome: a systematic review and meta-analysis. Hum Reprod Update 23(3):265–275

doi: 10.1093/humupd/dmx008

Salzano A, D’Assante R, Heaney LM, Monaco F, Rengo G, Valente P, Pasquali D, Bossone E, Gianfrilli D, Lenzi A, Cittadini A, Marra AM, Napoli R (2018) Klinefelter syndrome, insulin resistance, metabolic syndrome, and diabetes: review of literature and clinical perspectives. Endocrine 61(2):194–203. https://doi.org/10.1007/s12020-018-1584-1586

doi: 10.1007/s12020-018-1584-1586 pubmed: 29572708

Calogero AE, Giagulli VA, Mongioì LM, Triggiani V, Radicioni AF, Jannini EA, Pasquali D, Klinefelter ItaliaN Group (KING) (2017) Klinefelter syndrome: cardiovascular abnormalities and metabolic disorders. J Endocrinol Invest 40(7):705–712

doi: 10.1007/s40618-017-0619-9

Balercia G, Bonomi M, Giagulli VA, Lanfranco F, Rochira V, Giambersio A, Accardo G, Esposito D, Allasia S, Cangiano B, De Vincentis S, Condorelli RA, Calogero A, Pasquali D, KING group (2019) Thyroid function in Klinefelter syndrome: a multicentre study from KING group. J Endocrinol Invest 42:1199–1204

doi: 10.1007/s40618-019-01037-2

Accardo G, Vallone G, Esposito D, Barbato F, Renzullo A, Conzo G, Docimo G, Esposito K, Pasquali D (2015) Testicular parenchymal abnormalities in Klinefelter syndrome: a question of cancer? Examination of 40 consecutive patients. Asian J Androl 17(1):154–158

doi: 10.4103/1008-682X.128514

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

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

doi: 10.1111/andr.12080

Rita I, Ferrante E, Scalambrino E, Profka E, Clerici M, Lettera T, Serban AL, Vena W, Pizzocaro A, Bonomi M, Cangiano B, Carosi G, Mazziotti G, Persani L, Lania A, Arosio M, Peyvandi F, Mantovani G, Tripodi A (2021) Procoagulant imbalance in Klinefelter syndrome assessed by thrombin generation assay and whole blood thromboelastometry. J Clin Endocrinol Metab 106(4):1660–1672

doi: 10.1210/clinem/dgaa936

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):465–467

doi: 10.1111/cen.12245

Gravholt CH, Chang S, Wallentin M, Fedder J, Moore P, Klinefelter SA (2018) Syndrome: integrating genetics, neuropsychology, and endocrinology. Endocr Rev 39(4):389–423

doi: 10.1210/er.2017-00212

Swerdlow AJ, Higgins CD, Schoemaker MJ, Wright AF, Jacobs PA, United Kingdom Clinical Cytogenetics Group (2005) Mortality in patients with Klinefelter syndrome in Britain a cohort study. J Clin Endocrinol Metab 90(12):6516–6522

doi: 10.1210/jc.2005-1077

Bojesen A, Juul S, Birkebaek NH, Gravholt CH (2006) Morbidity in Klinefelter syndrome: a Danish register study based on hospital discharge diagnoses. J Clin Endocrinol Metab 91(4):1254–1260. https://doi.org/10.1210/jc.2005-0697

doi: 10.1210/jc.2005-0697 pubmed: 16394093

Vermeulen A, Verdonck L, Kaufman JM (1999) A critical evaluation of simple methods for the estimation of free testosterone in serum. J Clin Endocrinol Metab 84(10):3666–3672

doi: 10.1210/jcem.84.10.6079

Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (2001) Executive Summary of the third Report of the National Cholesterol Education Program (NCEP) Expert Panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III). JAMA 285(19):2486–2497. https://doi.org/10.1001/jama.285.19.2486

doi: 10.1001/jama.285.19.2486

Wang C, Baker HW, Burger HG, De Kretser DM, Hudson B (1975) Hormonal studies in Klinefelter’s syndrome. Clin Endocrinol (Oxf) 4(4):399–411

doi: 10.1111/j.1365-2265.1975.tb01547.x

Lanfranco F, Kamischke A, Zitzmann M, Nieschlag E (2004) Klinefelter’s syndrome. Lancet 364(9430):273–283

doi: 10.1016/S0140-6736(04)16678-6

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

doi: 10.2337/dc06-0145

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

Høst C, Bojesen A, Erlandsen M, Groth KA, Kristensen K, Jurik AG, Birkebæk NH, Gravholt CH (2019) A placebo-controlled randomized study with testosterone in Klinefelter syndrome: beneficial effects on body composition. Endocr Connect 8(9):1250–1261

doi: 10.1530/EC-19-0323

Pizzocaro A, Vena W, Condorelli R, Radicioni A, Rastrelli G, Pasquali D, Selice R, Ferlin A, Foresta C, Jannini EA, Maggi M, Lenzi A, Pivonello R, Isidori AM, Garolla A, Francavilla S, Corona G, KING, Klinefelter ItaliaN Group (2020) Testosterone treatment in male patients with Klinefelter syndrome: a systematic review and meta-analysis. J Endocrinol Invest 43(12):1675–1687

doi: 10.1007/s40618-020-01299-1

Grossmann M, Thomas MC, Panagiotopoulos S, Sharpe K, MacIsaac RJ, Clarke S, Zajac JD, Jerums G (2008) Low testosterone levels are common and associated with insulin resistance in men with diabetes. J Clin Endocrinol Metab 93(5):1834–1840

doi: 10.1210/jc.2007-2177

Grossmann M, Gianatti EJ, Zajac JD (2010) Testosterone and type 2 diabetes. Curr Opin Endocrinol Diabetes Obes 17(3):247–256

doi: 10.1097/MED.0b013e32833919cf

Selvin E, Feinleib M, Zhang L, Rohrmann S, Rifai N, Nelson WG, Dobs A, Basaria S, Golden SH, Platz EA (2007) Androgens and diabetes in men: results from the third National Health and Nutrition Examination Survey (NHANES III). Diabetes Care 30(2):234–238

doi: 10.2337/dc06-1579

Kanakis GA, Tsametis CP, Goulis DG (2019) Measuring testosterone in women and men. Maturitas 125:41–44

doi: 10.1016/j.maturitas.2019.04.203

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):518–523

doi: 10.1210/jc.2014-2780

Heufelder AE, Saad F, Bunck MC, Gooren L (2009) Fifty-two-week treatment with diet and exercise plus transdermal testosterone reverses the metabolic syndrome and improves glycemic control in men with newly diagnosed type 2 diabetes and subnormal plasma testosterone. J Androl 30(6):726–733

doi: 10.2164/jandrol.108.007005

Samuelson G (2000) Dietary habits and nutritional status in adolescents over Europe. An overview of current studies in the Nordic countries. Eur J Clin Nutr 54(1):S21–S28. https://doi.org/10.1038/sj.ejcn.1600980

doi: 10.1038/sj.ejcn.1600980 pubmed: 10805034

Cruz JA (2000) Dietary habits and nutritional status in adolescents over Europe-Southern Europe. Eur J Clin Nutr 54(1):S29-35

doi: 10.1038/sj.ejcn.1600981

Herlihy AS, Halliday JL, Cock ML, McLachlan RI (2011) The prevalence and diagnosis rates of Klinefelter syndrome: an Australian comparison. Med J Aust 194(1):24–28

doi: 10.5694/j.1326-5377.2011.tb04141.x

Gies I, Unuane D, Velkeniers B, De Schepper J (2014) Management of Klinefelter syndrome during transition. Eur J Endocrinol 171(2):R67-77. https://doi.org/10.1530/EJE-14-0213 (Epub 2014 May 6 PMID: 24801585)

doi: 10.1530/EJE-14-0213 pubmed: 24801585

Aksglaede L, Link K, Giwercman A, Jørgensen N, Skakkebaek NE, Juul A (2013) 47, XXY Klinefelter syndrome: clinical characteristics and age-specific recommendations for medical management. Am J Med Genet C Semin Med Genet 163C(1):55–63. https://doi.org/10.1002/ajmg.c.31349 (Epub 2013 Jan 23 PMID: 23345262)

doi: 10.1002/ajmg.c.31349 pubmed: 23345262

Garolla A, Selice R, Menegazzo M, Valente U, Zattoni F, Iafrate M, Prayer-Galetti T, Gardiman MP, Ferlin A, Di Nisio A, Foresta C (2018) Novelinsights on testicular volume and testosterone replacementtherapy in Klinefelter patients undergoing testicular sperm extraction. A retrospective clinical study. Clin Endocrinol (Oxf) 88:711–718

doi: 10.1111/cen.13572

Kanakis GA, Nieschlag E (2018) Klinefelter syndrome: more than hypogonadism. Metabolism 86:135–144

doi: 10.1016/j.metabol.2017.09.017

Zitzmann M, Aksglaede L, Corona G, Isidori AM, Juul A, T’Sjoen G, Kliesch S, D’Hauwers K, Toppari J, Słowikowska-Hilczer J, Tüttelmann F, Ferlin A (2021) European academy of andrology guidelines on Klinefelter syndrome endorsing organization: European Society of Endocrinology. Andrology 9(1):145–167

doi: 10.1111/andr.12909