Practice Easily Missed?

Klinefelter’s syndrome

BMJ 2012; 345 doi: http://dx.doi.org/10.1136/bmj.e7558 (Published 03 December 2012) Cite this as: BMJ 2012;345:e7558
  1. Christopher H Blevins, resident physician1,
  2. Michael E Wilson, instructor of medicine1
  1. 1Mayo Clinic Department of Medicine, 200 First Street SW, Rochester, Minnesota, MN 55905, USA
  1. Correspondence to: M E Wilson wilson.michael1{at}mayo.edu
  • Accepted 26 October 2012

A 29 year old man presented to primary care with anxiety and depression that had worsened since childhood. Further questioning revealed a history of poor school performance, poor body image, and poor self esteem. On physical examination, the patient’s height was 189 cm and he had narrow shoulders, wide hips, sparse facial hair (which he shaved once every two months), and small, firm testicles. He was found to have elevated luteinising hormone and follicular stimulating hormone concentrations, low serum concentrations of testosterone, absent sperm on semen analysis, and a karyotype of 47,XXY.

What is Klinefelter’s syndrome?

Klinefelter’s syndrome is the clinical result of an additional X chromosome in males (47,XXY), although other chromosome abnormalities (such as 46,XY/47,XXY mosaicism; 48,XXXY; 49,XXXXY) account for 10-20% of cases.1 2 Classic clinical findings include infertility, small testes, hypergonadotropic hypogonadism (elevated luteinising hormone and follicular stimulating hormone concentrations with low or low to normal testosterone concentrations), decreased facial and body hair, gynecomastia, tall stature with eunuchoid features, and psychosocial morbidity.1 3

How common is Klinefelter’s syndrome?

  • Klinefelter’s syndrome affects 1 in 667 live male births and is the most common sex chromosome disorder4

  • Large population based studies confirm that more than 90% of boys with Klinefelter’s syndrome aged 10-14 years and about 75% of men with the syndrome aged 25-54 years remain undiagnosed4

Why is Klinefelter’s syndrome missed?

Although virtually all men with Klinefelter’s syndrome have infertility and small testes, there is wide variability in the frequency of other phenotypic features (table 1). Additionally, the classic phenotypic features may not all be present simultaneously.5 Many individuals with Klinefelter’s syndrome may have subtle clinical findings, especially prepubertal boys and men affected with mosaic forms.2 8 Individuals with subtle clinical findings may not present for medical evaluation until later in life when hypogonadism, sexual dysfunction, or infertility become apparent.3 Furthermore, a lack of awareness among physicians about Klinefelter’s syndrome contributes to a delay in diagnosis in nearly 60% of cases.2

Table 1

 Estimated frequencies of clinical features of Klinefelter’s syndrome

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Why does this matter?

Klinefelter’s syndrome has been associated with several complications, many of which are secondary to chronic untreated hypogonadism (table 2). Early recognition of hypogonadism can lead to appropriate management and prevention of associated outcomes.2 8 Complications such as diabetes, cardiovascular disease, pulmonary embolism, and peripheral vascular disease have been associated with increased mortality rates in patients with Klinefelter’s syndrome.16 In addition, early recognition of psychosocial morbidity can facilitate speech therapy and educational support, which improve scholastic performance.5 17 Cryopreservation of any sperm identified at the early onset of puberty (before most of the germ cell destruction has occurred) may enhance future attempts to increase fertility by using techniques such as intracytoplasmic sperm injection.18

Table 2

 Estimated frequencies of clinical conditions associated with Klinefelter’s syndrome

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How is Klinefelter’s syndrome diagnosed?

Clinical features

The classic clinical description includes infertility; small firm testes; decreased facial and pubic hair; tall, slender body habitus (with long legs, narrow shoulders, and wide hips); gynecomastia or history of gynecomastia during puberty; decreased libido; history of cryptoorchidism; learning disability; delayed speech development; behavioural problems; and psychosocial disturbances. Although infertility and small testes are present in about 99% of individuals, other clinical features are present with varying frequencies (table 1), and many individuals may have only subtle clinical features. The presence of any one of the listed features may warrant further investigation for Klinefelter’s syndrome.

Investigations

If the clinical assessment suggests Klinefelter’s syndrome, luteinising hormone, follicular stimulating hormone, and testosterone concentrations should be obtained. In post-pubescent males, this will typically show hypergonadotropic hypogonadism (always elevated luteinising hormone and follicular stimulating hormone concentrations with usually low or low to normal testosterone concentrations).3 8 Testosterone, luteinising hormone, and follicular stimulating hormone concentrations are usually normal in prepubescent males. If the patient has abnormal gonadotropin concentrations, then specialty referral for confirmatory testing with chromosome analysis is warranted. For patients with infertility or hypogonadism arrange a semen analysis. Once Klinefelter’s syndrome has been confirmed, consider screening for diabetes, dyslipidemia, and osteoporosis.1

How is Klinefelter’s syndrome managed?

Consider testosterone replacement, starting at puberty, if there is clinical evidence of androgen deprivation.5 In patients with Klinefelter’s syndrome, testosterone replacement therapy improves mood, muscle strength, libido, self esteem, and behavioral difficulties; increases body hair; reduces fatigue; and has been associated with improved cardiovascular outcomes and increased bone mineral density.2 Additional treatment modalities include a multidisciplinary neurodevelopmental and psychosocial assessment. Speech and behavioral therapy, providing individualised school assistance, and treating any associated psychiatric conditions are warranted.19 Infertility does not improve with testosterone replacement, although advanced techniques such as microsurgical testicular sperm extraction and intracytoplasmic sperm injection have achieved limited success.1 Finally, providing patients with access to support groups may be beneficial—for example, in the United Kingdom, the Klinefelter’s Syndrome Association (www.ksa-uk.co.uk), and in the United States the KS&A (www.genetic.org).

Key points

  • Klinefelter’s syndrome (47,XXY) has wide phenotypic variability. Small testes and infertility are present in almost all patients. More variable clinical findings include decreased facial and pubic hair; tall, slender body habitus; history of gynecomastia; decreased libido; and learning disabilities or psychosocial or behavioral concerns

  • If Klinefelter’s syndrome is suspected, check serum luteinising hormone, follicular stimulating hormone, and testosterone concentrations; if gonadotropin concentrations are abnormal, consider specialty referral and chromosome analysis

  • Klinefelter’s syndrome is associated with increased risk of osteoporosis, diabetes mellitus, venous thromboembolism, and breast cancer

Notes

Cite this as: BMJ 2012;345:e7558

Footnotes

  • This is one of a series of occasional articles highlighting conditions that may be more common than many doctors realise or may be missed at first presentation. The series advisers are Anthony Harnden, university lecturer in general practice, Department of Primary Health Care, University of Oxford, and Richard Lehman, general practitioner, Banbury. To suggest a topic for this series, please email us at easilymissed{at}bmj.com.

  • Contributors: Both authors contributed to the planning, drafting, revising, and final approval of the article. MEW is the guarantor.

  • Competing interests: Both authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.

  • Provenance and peer review: Not commissioned; externally peer reviewed.

  • Patient consent not required (patient anonymised, dead, or hypothetical).

References