Course:MEDG550/Student Activities/Kleinfelter Syndrome

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Klinefelter syndrome is a genetic condition in which a male is born with an extra copy of the X chromosome, resulting in 3 copies of the sex chromosomes (XXY) instead of the typical 2 copies that are seen (XY). This extra X chromosome results in decreased testicular function and decreased testosterone production - the sex hormone that promotes male sexual development before birth and during puberty. Klinefelter syndrome is characterized by reduced muscle mass, increased breast tissue, small testicles, infertility and reduced body/facial hair. A relatively common condition affecting 1 in 500 to 1 in 1,000,[1] it often goes undiagnosed as the symptoms are mild and vary from person to person – not every man with Klinefelter syndrome will present with the same features.

Clinical Features

Cartoon representation of the clinical symptoms of Klinefelter syndrome.

Men with Klinefelter syndrome vary in their features, and may have any or all of the following:

  • Small testes
  • Decreased testosterone, resulting in:
    • Delayed puberty
    • Breast enlargement (gynecomastia)
    • Infertility
  • Genital differences
  • Children and adults taller than peers
  • Increased risk of breast cancer compared to XY males


Because the presentation of Klinefelter syndrome can be mild, many men often go undiagnosed. Different options exist to test for the condition:

  • Karyotype:
A karyotype is a microscopic chromosome analysis, examining the number, shape and quality of all 46 chromosomes (or 47 in the case of Klinefelter syndrome). DNA taken from a blood sample can be used to generate a karyotype. This type of test is definitive - it will clearly confirm or deny the diagnosis of Klinefelter syndrome on the basis of the presence or absence of an extra sex chromosome.
  • Hormone Investigation:
As testosterone production is deficient in men with Klinefelter syndrome, a blood or urine sample can reveal abnormal hormone levels that may be associated with Klinefelter syndrome. However, abnormal hormone production can result from a number of causes - this test is therefore an indication of Klinefelter, and is not as absolute as a chromosomal analysis.[2]

Klinefelter syndrome variants

While Klinefelter syndrome refers specifically to the presence of an extra X chromosome in males (XXY), additional X chromosomes (XXXY, XXXXY) result in disorders with similar effects; these conditions are referred to as variants of Klinefelter syndrome. Men with variants of Klinefelter syndrome often have more exaggerated signs and symptoms than men with the classic syndrome. In addition to the above symptoms, men with variants of Klinefelter syndrome may have distinctive facial features, intellectual disability, skeletal abnormalities, poor coordination, and extreme difficulty with speech[3][4]. In general, the severity of the clinical features increases with the presence of more X chromosomes [5].


Testosterone treatment

Since testosterone production is compromised in XXY men, hormone supplementation can assist in male sexual development during puberty. Around 12 years of age, androgen (male sex hormone) replacement therapy ensures appropriate serum concentrations of testosterone, estradiol, follicle stimulating hormone (FSH) and luteinizing hormone (LH). [6] Though androgen replacement therapy does not treat small testes, gynecomastis or infertility, it encourages normal development of male secondary sex characteristics, normal body proportions, and general improement in behavior and work performance.[7] Further, androgen treatment is thought to reduce the risk of breast cancer,[8] which is elevated in men with Klinefelter relative to XY men.[9]

Speech therapy

The development of complex language in men with Klinefelter syndrome is markedly improved with early speech and language therapy.[10]

Physical & Occupational therapy

Boys with Klinefelter syndrome may present with reduced muscle tone (hypotonia) and delays in their gross motor skills (large movements with arms, legs, feed and/or entire body); in these circumstances, muscle tone, balance and coordination may be affected, and boys would benefit from physical therapy. In cases where fine motor control (fingers, toes, wrists) is impacted or feeding is difficult in infancy, occupational therapy is recommended.[11]

Educational services

Access to additional educational resources requires a thorough psychoeducational examination early on to identify a child's strengths and weaknesses, so that aid can be appropriately allocated. A discussion with a developmental-behavioral pediatrician is recommended, with the aim of planning specific resources and appropriate classroom placement.


Human DNA is condensed and packaged into structures called chromosomes; along each chromosome are smaller segments called genes that give our body instructions for making different proteins essential for everyday life. Normally, every cell in our body contains 23 pairs of each chromosome - one of each pair of maternal origin, the other of paternal origin. 22 of these chromosomes pairs are shared between men and women, but the fundamental difference between men and women lies in the 23rd pair of chromosomes, termed the sex chromosomes. Male sex is defined by the presence of one X and one Y chromosome, while females have two X chromosomes. Men affected with Klinefelter syndrome have a an extra copy of the X chromosome, and all of the genes encompassed within it, which is responsible for their clinical features.

An artistic depiction of a karyotype of a man with Klinefelter syndrome. There are 22 pairs of autosomes present, but 3 sex chromosomes (XXY, circled)

The presence of the extra X chromosome occurs by chance through a process called non-disjunction. During maturation and development, sperm and egg cells (gametes) undergo a series of divisions (meiosis) that ends with each gamete having only one copy of each chromosome (23 total chromosomes). Thus, upon the union of one egg and one sperm, the resulting embryo will have 2 copies of each chromosome - a complete set. However, random errors during these divisions (non-disjunction) can cause unequal distribution of chromosomes to sperm and egg cells. Klinefelter syndrome is caused by an extra sex chromosome in a parent's egg or sperm (XX or XY) which then gains another sex chromosome (Y or X, respectively) during fertilization, resulting in an embryo that is XXY.

Genetic Counselling


Non-disjunction is a sporadic, random event that causes Klinefelter syndrome and is therefore not inherited; if you have one child with Klinefelter syndrome, your risk for having another child with the condition is not increased above the baseline population risk. Men with Klinefelter syndrome who wish to father children through assisted reproductive technology are not at increased risk of producing sperm with extra copies of the sex chromosomes[12].

Infertility and Assisted Reproductive Technology

Achieving a pregnancy was previously not thought possible in many men with Klinefelter syndrome, as these men do not have sperm in their semen (azoospermia). However, through assisted reproductive technology, doctors can find sperm by means of microsurgical testicular sperm extraction (TESE). This involves taking a microscopic testicular biopsy near the site of sperm production; if a man's sperm can be extracted from this biopsy, the sperm can be used to fertilize his partner's eggs in a procedure called in vitro fertilization with intracytoplasmic sperm injection (IVF with ICSI). Because the sperm have not yet fully matured, they do not move efficiently and are incapable of fertilizing an egg on their own. ICSI therefore allows for the direct injection of a sperm into an egg extracted from the mother, which can then grow, mature and ultimately be implanted into the mother[13].


The Association for X and Y Chromosome Variations

Klinefelter Syndrome Global Support Group

The American Association for Klinefelter Syndrome Information and Support

  1. Genetics Home Reference, 2013
  2. Mayo Clinic, 2016
  3. Visootsak J, Aylstock M, Graham JM Jr. Klinefelter syndrome and its variants: an update and review for the primary pediatrician. Clin Pediatr (Phila). 2001 Dec;40(12):639-51. Review.
  4. Frühmesser A, Kotzot D. Chromosomal variants in klinefelter syndrome. Sex Dev. 2011;5(3):109-23. doi: 10.1159/000327324. Epub 2011 Apr 29. Review.
  5. Tartaglia N, Ayari N, Howell S, D'Epagnier C, Zeitler P. 48,XXYY, 48,XXXY and 49,XXXXY syndromes: not just variants of Klinefelter syndrome. Acta Paediatr. 2011 Jun;100(6):851-60. doi: 10.1111/j.1651-2227.2011.02235.x. Epub 2011 Apr 8. Review.
  6. Visootsak J, Graham Jr J. Klinefelter syndrome and other sex chromosomal aneuploidies. Orphanet J Rare Dis. 2006 Oct;1:42
  7. Nielsen J, Pelsen B, Sorensen K. Follow-up of 30 Klinefelter males treated with testosterone. Clin Genet. 1988;33:262–269
  8. Kocar IH, Yesilova Z, Ozata M, Turan M, Sengul A, Ozdemir I. The effect of testosterone replacement treatment on immunological features of patients with Klinefelter's syndrome. Clin Exp Immunol. 2000;121:448–452
  9. Brinton LA. Breast cancer risk among patients with Klinefelter syndrome. Acta Paediatr. 2011 Jun; 100(6): 814-8
  10. Visootsak J, Graham Jr J. Klinefelter syndrome and other sex chromosomal aneuploidies. Orphanet J Rare Dis. 2006 Oct;1:42
  11. Visootsak J, Graham Jr J. Klinefelter syndrome and other sex chromosomal aneuploidies. Orphanet J Rare Dis. 2006 Oct;1:42
  12. Bergère M, Wainer R, Nataf V, et al. Biopsied testis cells of four 47,XXY patients: fluorescence in‐situ hybridization and ICSI results. Hum Reprod. 2002;17:32‐37
  13. Tournaye H, Camus M, Vandervorst M, Nagy Z, Joris H, Van Steirteghem A, Devroey P. Surgical sperm retrieval for intracytoplasmic sperm injection. Int J Androl. 1997; 20 Sppl 3:69-73