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Klinefelter's syndrome

Klinefelter’s syndrome is the most common sex chromosome disorder in man and a relatively common cause of male infertility and hypogonadism ( Anders Bojesen et al 2011 )
How common –Only men are affected First defined in 1942 by Harry Klinefelter in males who had small testes , gynaecomastia , and no ability for spermatogenesis ( Boston , Massachusetts ) Most common sex chromosome disorder due an extra X chromosome which can be inherited from either parent KS affects all racial groups and ethnicities equally KS has an estimated prevalence of between 1: 500 to 1: 1000 males Underdiagnosis is common and is widely reported in literature ( 50-60 % of cases ) Mean age of diagnosis is in mid 30s KS is responsible for 3 % of male infertility KS is common in infertile men with oligospermia or azoospermia ( 5 % to 10 % ) Most frequent form of male hypogonadism.
Karyotypes –47 , XXY usually called the classic type is the most common seen in 80 % to 90 % of KS cases.
Rest 10 % to 20 % may have
 46 XY / 47 , XXY Mosaic form ( some cells have extra X chromosome and others have normal male chromosome ) Other aneuploidies such as 48 , XXXY and 49 ,XXXXY X chromosome structural abnormalities
A broad spectrum of phenotypes have been described Aneuploidy happens when an individual has an abnormal number of chromosomes in a cell. Mosaicism ( ie different karyotype in different cells ) typically have less severe phenotype than men with a 47 , XXY karyotype Presence of higher number of X chromosomes ( e.g 48 , XXXY ) results in a more severe phenotype with profound learning difficulties and dysmorphic features
What happens -Due to non-disjunction ie failure of homologous chromosomes to separate at anaphase Testosterone deficiency ( hyperplastic Leydig cells cannot produce enough testosterone ) Unsuppressed FSH and LH hormones Primordial germ cells ( stem cells ) are exhausted by puberty and very few seminiferous tubules with complete spermatogenesis In adult patient with KS
- testosterone , insulin like factor , inhibin B & anti-Mullerian hormone are reduced
- FSH / LH are elevated
- 17 beta estradiol and SHBG are comparable to control.
Why important -Increased morbidity and mortality ( 50 % increase in mortality risk ) Increased risk of hospital admission ( mainly due to congenital malformations , psychiatric , endocrime and metabolic disorders ) Impaired metabolic profile ( obesity , dyslipidemia and insulin resistance ) Tendency to thrombosis Increased risk of cardiovascular disease , diabetes Susceptibility to specific cancers as breast , extragonadal germ cell tumours At increased risk of autoimmune diseases Increased risk osteoporosis and bone fracture Poor intellectual abilities and function –> low socioeconomic status.
Prenatal diagnosis is possible
 Karyotype evaluation of the pleural fluid in amniocentesis Routine US does not show any significant features Not included in routine screening It is estimated that currently only about 10 % of cases are detected prenatally ( for e.g amniocentesis for some other reason )
Infants- No specific features during delivery , but infants may be seen to have Congenital malformations as clinodactyly , cleft palate and inguinal hernia Cardiological abnormalities and radioulnar synostosis Disorders of testicular descent
Childhood -Size of penis and testicular volume is smaller Accelerated growth from early childhood -> taller than controls ( mainly due to abnormally long legs ) Adnominal obesity Learning difficulties Delayed development milestones for e.g in speech and movement Low muscle tone and resulting co-morbidities as chronic constipation , sleep apnoea , abnormal posturing Language and learning problems for e.g difficulty with reading / spelling Impairment on verbal and non verbal memory and in executive function Aggressiveness and non-compliance
Puberty-Abscence of testicular volume ( < 4 ml ) – testicles become rigid due to hyalanization and fibrosis ( testicles not getting bigger despite development of 2ary sexual charecters ) Gynaecomastia ( due to androgen aromatization ) Taller than peers ( long limbs -low upper / lower segment ratio ie the lower extremity is disproportionately longer , in comparison to the upper extremity )
Normal development of secondary sexual characters No abnormalities may be noted in axillary/ pubic hair development , increase in penis size , increase in muscle mass , beard moustache development and sound quality Patients with mosacism may not have any typical features Depression KS is often diagnosed when a boy fails to progress through puberty completely or inadequately or breast development starts
Adults -Often diagnosed during investigations for infertility / hypogonadism and or sexual dysfunction Hypergonadorophic hypogonadism Small testes H/O learning difficulty and behavioral issues Sexual function as erection and ejaculation are often normal Patients particularly with azoospermia should be reviwed after excluding other causes

Patients may be diagnosed due to association of KS with different medical presentations involving congenital malformations , psychiatric , endocrine and metabolic problems.
Tests-Result of biochemical invetigations may vary over time
- gradually decreases over time
- rises with puberty and may rise to lower levels of normal
- normal levels may be seen in mosaic forms
 FSH -elevation is more than LH , but both are elevated above normal
 Testicular volume < 4 ml
 Karyotyping ( can be lymphoctyic , complimentary FISH study type , from skin fibroblasts or testicular biopsy ) can estabilish the diagnosis 
 KS can be diagnosed at any age.
No cure exists for KS but several treatment options exist to improve QOL and alleviate symptoms
 Treatment is multi-disciplinary which can involve speech therapists , psychologists , GPs , paediatricians , endocrinologists , urologists and infertility specialists
 Earlier diagnosis allows for earlier developmental evlauation and interventions to aid with neuropsychological development. Early intervention is proven to be beneficial.Testosterone replacement thetapy ( TRT ) can help prevent many of the comorbidities ( related to hypogonadism ) and have a positive effect on the general health and QOL
 Cryopreservation of sperm -oferred to adolescent KS patients who are able to provide a semen sample for e.g Testicular sperm extraction
 Gynaecomastia – cannot be treated but patients are at higher risk of breast cancer and need to be checked for this regularly
 Monitoring for comorbidities in primary care fo e.g – routine monitoring
- FBC , TFT , Lipids , fasting glucose
- DEXA scan

Primary care plays an important role in early detection of sexual dysfunction , malignancy , tooth decay , autoimmune diseases and thyroid dysfunction.

  1. Los E, Ford GA. Klinefelter Syndrome. [Updated 2020 Jul 19]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan-. Available from:
  2. Hormones and Me Klinefelter Syndrome Australasian Paediatric Endocrine Group
  3. Kanakis GA, Nieschlag E, Klinefelter syndrome: more than hypogonadism, Metabolism Clinical and Experimental(2018),
  4. Arshad M.A., Yamani M.M.A.O., Elbardisi H.T., Majzoub A. (2020) Novel Approaches in the Management of Klinefelter Syndrome. In: Parekattil S., Esteves S., Agarwal A. (eds) Male Infertility. Springer, Cham. ( Abstract )

  5. Nieschlag, E., Ferlin, A., Gravholt, C.H., Gromoll, J., Köhler, B., Lejeune, H., Rogol, A.D. and Wistuba, J. (2016), The Klinefelter syndrome: current management and research challenges. Andrology, 4: 545-549.
    Management of Klinefelter syndrome
    during transition
    Inge Gies1,3,†, David Unuane2,3, Brigitte Velkeniers2,3 and Jean De Schepper1,2,3
    Division of Pediatric Endocrinology, Department of Endocrinology and 3
    Klinefelter Clinic, UZ Brussel,Vrije Universiteit Brussel, Brussels, Belgium
    (I Gies is now at Department of Pediatrics, UZ Brussel, Laarbeeklaan 101, 1090 Brussels, Belgium)
  7. Bojesen, A. and Gravholt, C.H. (2011), Morbidity and mortality in Klinefelter syndrome (47,XXY). Acta Paediatrica, 100: 807-813. (Abstract )
  8. Klinefelter syndrome: a general practice perspective Elyssia BourkeAmy HerlihyPamela SnowSylvia MetcalfeDavid Amor AUSTRALIAN FAMILY PHYSICIAN VOL. 43, NO. 1–2, JANUARY– FEBRUARY 2014
  9. Kristian A. Groth, Anne Skakkebæk, Christian Høst, Claus Højbjerg Gravholt, Anders Bojesen, Klinefelter Syndrome—A Clinical Update, The Journal of Clinical Endocrinology & Metabolism, Volume 98, Issue 1, 1 January 2013, Pages 20–30,
  10. Klinefelter syndrome: cardiovascular abnormalities and metabolic disordersA. E. Calogero1 · V. A. Giagulli2 · L. M. Mongioì1 · V. Triggiani3 · A. F. Radicioni4 · E. A. Jannini5 · D. Pasquali6 · On behalf of the Klinefelter ItaliaN Group (KING) J Endocrinol Invest (2017) 40:705–712 DOI 10.1007/s40618-017-0619-9
  11. KlinefelterSyndrome‐XXY by Kara Dragan
  12. Klinefelter SyndromeDANIEL J. WATTENDORF, MAJ, MC, USAF, and MAXIMILIAN MUENKE, M.D. National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland
  13. Wattendorf DJ, Muenke M. Klinefelter syndrome. Am Fam Physician. 2005 Dec 1;72(11):2259-62. PMID: 16342850.
  14. Klinefelter Syndrome Hande Peynirci, Erdinç Ertürk
    Uludağ University School of Medicine, Department of Endocrinology, Bursa, Turkey Turk Jem 2013; 17: 63-7
  15. Nieschlag, Eberhard. “Klinefelter syndrome: the commonest form of hypogonadism, but often overlooked or untreated.” Deutsches Arzteblatt international vol. 110,20 (2013): 347-53. doi:10.3238/arztebl.2013.0347



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