Klinefelter Syndrome

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Klinefelter Syndrome (KS) is a chromosomal disorder which occurs when an individual’s karyotype is XY (male), and there is at least one additional X chromosome.1

The incidence of KS is estimated to be about 1.5 in 1000 live-born males.1,2 While the clinical manifestations of KS vary widely, its subtle signs and phenotype may not be apparent until adulthood. Only 25 to 50% of affected males manage to obtain a diagnosis during their lifetime.3

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TheΒ XΒ andΒ Y chromosomesΒ are the sex chromosomes, withΒ femalesΒ havingΒ XX sex chromosomesΒ andΒ malesΒ havingΒ XY sex chromosomes.

In Klinefelter syndrome, there is the presence of at least one additional X chromosome, resulting in a karyotype of 47, XXY (or, rarely, even more, extra X chromosomes).1

KS typically occurs via one of the following processes:1,4

  • Meiotic non-disjunction of the X chromosome from the maternal or paternal side, leading to the formation of sperm or egg cells with an abnormal number of chromosomes during gametogenesis (80-90%)
  • Mosaicism during early foetal growth (10%)

KS typically have longer cytosine, adenine and guanine (CAG) repeats in the androgen receptor gene. The shorter the CAG repeat, the more sensitive the androgen receptor is towards testosterone. Therefore, in the case of KS, the severity of the phenotype is inversely proportional to the long length of the CAG repeat.5,6

It is important to note that, like other chromosomal abnormalities, Klinefelter syndrome affects many more pregnancies, but around 60% of these will spontaneously abort.

Risk factors

Advanced maternal age is the only evidence-based risk factor for KS.7,8

Clinical features

Due to the variability in phenotype severity and difficulty in recognising the clinical signs of KF, the mean age of diagnosis is around 30.1

Otherwise, the typical presentations differ by developmental stage and level of expression. The phenotype of Klinefelter is affected by androgen responsiveness – as KS is one of the commonest causes of primary hypogonadism.5,6


Neonates and pre-pubertal boys

Only the most severe phenotypes of KS are recognised before puberty. Β In young boys, there may be noticeable language delay and behavioural abnormalities.9,10


Patients with KS will often have abnormal pubertal development, and so may report symptoms related to delayed development of secondary sexual characteristics, or issues such as gynaecomastia.11,12Β Issues with developmental delay and behaviour may also become more noticeable as patients age.


Most adult men present with infertility and signs and symptoms of androgen deficiency, such as gynaecomastia and sexual complaints, most commonly erectile dysfunction and reduced libido.Β 

Clinical examination

Neonates and pre-pubertal boys

Most children appear to be normal at birth.13,14 The most distinguishing features of hypogonadism in the neonate are genital anomalies:11

  • Cryptorchidism
  • Micropenis (<1.9cm in full-term neonates)
  • Hypospadias


Many affected males present with absent or arrested pubertal development. This may include:Β 11,12

  • Small testicular size
  • Incomplete virilization (e.g. decreased pubic and facial hair, micropenis)
  • Gynaecomastia

The patient may also be taller than expected based on mid-parental height due to the lack of testosterone, leading to delayed epiphyseal fusion.12


Evaluation of genitalia would reveal:12-14

  • Small, firm testes: with a volume of ≀4 mL each
  • Inadequate phallic growth

This occurs due to extensive and progressive fibrosis of the seminiferous tubules, with little remaining foci of spermatogenesis.14

Differential diagnosis

The main differential diagnosis for KS would be Kallman syndrome – which is another possible cause of hypogonadism.17

Another differential would be androgen insensitivity syndrome (AIS), where affected patients have a 46,XY karyotype, but experience androgen insensitivity because of deactivating mutations in the androgen receptor gene.18


Prenatal investigations

Prenatal screening can be done by testing the maternal blood sample for the foetus’ cell-free DNA (cfDNA) that the placenta would have released into the mother’s bloodstream.1,19 Karyotyping may then be carried out.

The diagnosis may be further confirmed by karyotyping the cells from prenatal amniocentesis or chorion villus sampling.1

Postnatal investigations

KS is often diagnosed based on the clinical presentation and confirmatory laboratory testing, such as peripheral karyotyping.1 Evaluation of the sex chromosomes would demonstrate more than one X chromosome plus a Y chromosome.1,4

This test can be carried out at any age of males in whom a diagnosis of KS would be possible.

Peripubertal and adult investigations

The typical findings in pubertal boys and adult men are the following:

  • Serum FSH and LH: high in Klinefelter Syndrome2,4,14
  • Serum sex hormone-binding globulin (SHBG):Β high in Klinefelter Syndrome2
  • Serum total and free testosterone: both are low in Klinefelter Syndrome; however, due to SHBG concentrations being elevated, the serum free testosterone concentrations are disproportionately less than the serum total testosterone concentrations2,4,14

The elevated gonadotropins and decrease in androgen production, is known as hypergonadotropic hypogonadism, and is a hallmark for the characteristic phenotype of a man with KS.1,2,7,8,20,21

  • Semen analysis test: azoospermia is usually reported on sperm count analysis1


As discussed above, the diagnosis of KS would be confirmed by the presence of additional X chromosomes on karyotyping of an individual with a Y chromosome.

If genetic mosaicism is suspected as the cause, then karyotyping is often carried out on cells from the patient’s oral mucosa to confirm this.


The current guidelines present recommendations for managing patients with KS, according to age of diagnosis, severity of phenotype and desired clinical endpoint.24

Patients require multidisciplinary team input, and those involved may include:1,2,24

  • Paediatricians
  • GPs
  • Endocrinologists
  • Psychologists
  • Speech and language therapists
  • Specialist nurses
  • Fertility experts

Testosterone therapy is routinely offered to patients diagnosed with KS as it is the most important component of acute and long-term management for the possible consequences of hypogonadism. In boys of pubertal age and men, the goal would be to stimulate the gradual development of secondary sexual characteristics while also preventing the frequent associated comorbdities.1,2,8,9,24

Males who are infertile and interested in having children should be guided about the current options available.1,9,24

In addition to the above, patients will require management for the complications and co-morbidities associated with KS.


KS is associated with several complications and co-morbidities in many systems of the body:1,2,9,11,14,17,20,21,22,23

Cardiovascular disease

Endocrinological disease

Cancer risk

  • Increased risk, particularly that of breast cancer
  • Non-Hodgkin’s lymphoma
  • Germ cell tumours of the mediastinum

Cognitive and neuropsychiatric abnormalities

Key points

  • Klinefelter Syndrome occurs when there is a at least one extra X chromosome in an individual with Y chromosomes.
  • Clinical features are of varying severity, including signs of primary hypogonadism.
  • The diagnosis is often missed due to the subtle clinical manifestation of the Klinefelter syndrome.
  • If suspected, Klinefelter syndrome is confirmed by karyotyping of the sex chromosomes.
  • Multiple comorbidities have been linked to Klinefelter syndrome, including cardiovascular, endocrinological, oncological and neuropsychiatric abnormalities.
  • Management should be tailored for the patient’s needs and the importance of a multi-disciplinary team should not be underestimated. Testosterone therapy is also often considered.


Dr John Torpiano

Consultant Paediatric Endocrinologist


Dr Jess Speller


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  2. Groth, K. A., SkakkebΓ¦k, A., HΓΈst, C., Gravholt, C. H., & Bojesen, A. (2013). Klinefelter syndrome – A clinical update. In Journal of Clinical Endocrinology and Metabolism (Vol. 98, Issue 1, pp. 20–30).
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