By Zaira Salvador BSc, MSc (embryologist) and José Luis de Pablo BSc, MSc, PhD (senior clinical embryologist).
Last Update: 09/21/2018

Klinefelter syndrome (KS), also known as XXY syndrome, is a genetic cause of male infertility. Children born with this genetic disease have an extra X chromosome, hence the name. Their karyotype is 47,XXY.

The effects of having an additional chromosome are abnormalities in the normal development of the body, hypogonadism, and male infertility.

However, some men affected with Klinefelter syndrome have become been able to have healthy children thanks to Assisted Reproductive Technologies (ART).

Definition

Klinefelter or XXY syndrome is a genetic disease that causes babies to be born with an extra X chromosome. As a result, the baby has three sex chromosomes instead of 2, with male sex.

Even though the 47, XXY trisomy is the most common type, it is also possible to find males with abnormalities like 48,XXXY and 49,XXXXY in 20% of the cases approximately. It is estimated, however, that about 50% of the embryos with this chromosomal anomaly end up in miscarriage. The prevalence is 1 in every 1000 live births.

Phenotype of males

Signs and symptoms associated with children with Klinefelter syndrome start being noticeable during puberty, due to the absence of testosterone production. It is at this point when the male reproductive system and secondary male sex characteristics are supposed to develop.

Even though the physical features may vary on a case-by-case basis, the following are the most common ones:

  • Abnormal body proportions: too long legs, short trunk, shoulder equal to hip…
  • Absent or sparse facial, body and sexual hair
  • Poor muscle development
  • Gynecomastia or enlarged male breasts
  • Small or underdeveloped testes
  • Other alterations of the male reproductive system: micropenis, cryptorchidism, absent vasa deferentia…
  • Infertility due to azoospermia and diminished sex drive

Additionally, children affected with Klinefelter syndrome can develop psychological issues and behavioral problems. Although their IQ is generally normal, hyperactivity and attention-deficit disorder are usually associated with this chromosomal condition. Emotional disorders, depression, low self-confidence, etc. are common as well.

Causes

The fact that an embryo grows with an extra X chromosome is due to an error at some point of the meiosis process during gametogenesis (egg and sperm formation) in the parents.

Meiosis is a cell division process that occurs in the egg cells of the ovaries, and the sperm cells of the testicles. The goal is to create haploid gametes, that is, to reduce the number of chromosomes in a parent diploid cell by half.

To be precise, Klinefelter syndrome can be caused by nondisjunction of a pair of chromosomes: X chromosomes do not separate during prophase of meiosis I in females.

The result is an imbalance in the total number of sex chromosomes: while some gametes will contain two sex chromosomes, other won’t have any.

Depending on whether nondisjunction is associated with the father or the mother, we can distinguish two different case scenarios:

Errors during oogenesis
The eggs produced contain two X chromosomes instead of a single one.
Errors during spermatogenesis
The sperms produced contain a X chromosome and a Y chromosome, instead of a single X or Y chromosome.

When fertilization occurs between an affected and a healthy chromosome, the result is a triploid embryo (47, XXY).

It should be noted, however, that Klinefelter syndrome is more often associated with errors during oogenesis than spermatogenesis.

Less frequently, this chromosomal condition may appear during the earliest embryo cleavage, right after fertilization. In this case, they are called mosaic embryos.

Mosaicism occurs when two cell populations with different genotypes are present within the same embryo. In other words, half are chromosomally healthy, and the other half has the XXY trisomy.

Diagnosis

In most cases, Klinefelter syndrome is diagnosed when the boy is a teenager, due to obvious phenotype and psychological traits.

When these signs and symptoms are not so noticeable, males find out about this chromosomal condition when they start trying to conceive and realize that they have azoospermia.

It is at this point when they visit a fertility specialist and undergo the following tests in order to determine whether they suffer from KS or not:

Karyotype testing
Study of the number of chromosomes to detect the presence of an extra X chromosome.
Hormonal testing
To detect potential alterations in sex hormones, such as too increases levels of FSH, and diminished levels of testosterone.
Semen analysis report
Zero sperm count due to azoospermia.

If not detected at this stage, Klinefelter syndrome may be detected during pregnancy after doing an amniocentesis or amnio test, or a chorionic biopsy.

KS and fertility

Klinefelter syndrome is the most common cause of non-obstructive or secretory azoospermia in males. Having zero sperm count in the ejaculate is due to problems during spermatogenesis in the testicles.

In spite of that, sometimes males affected by KS present a few sperms in the ejaculate, which could translate into an opportunity to have biological children. Unfortunately, these sperms may be aneuploid and the risk of passing the disease to offspring would be considerably high.

Also, the presence of this trisomy in embryos may be a cause of recurrent miscarriage as well. In certain cases, mosaicism has been found to be the cause of repeated miscarriages.

Based on the number of affected cells by KS, the chances of producing abnormal sperm cells, and subsequently causing miscarriage or the birth of an ill child, will be higher or lower.

Treatment

Given that the Klinefelter syndrome is a genetic disease, actually there is no effective treatment to cure it.

However, opting for a hormone replacement therapy with testosterone can help improve the physical symptoms associated with reduced levels of this hormone. For instance, to trigger hair growth, build body mass, improve libido, etc.

Fertility treatment options

As for the treatment options to have a child, men affected by KS have no alternative but to become parents through a fertility treatment.

Firstly, to try to find viable sperm cells in cases of azoospermia causes by KS, and secondly, to prevent that this chromosomal condition is inherited by offspring.

So, in short, there exist various fertility treatment options for these patients:

Testicular biopsy & ICSI
When the sperm count is zero, performing a testicular biopsy to retrieve and use them for an ICSI cycle is an option.
Preimplantation Genetic Diagnosis (PGD)
The goal is to evaluate the embryos genetically in order to dismiss those with chromosomal abnormalities and use the healthy ones for the transfer.
Artificial insemination by donor (AID)
In case no sperms are found or the patient doesn’t want to run the risk of passing the disease to offspring, using donor sperm for IUI is an option.

You may also enjoy some further information reading this: Using a Sperm Donor to Get Pregnant.

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FAQs from users

Is Klinefelter syndrome a genetic disease?

By José Luis de Pablo BSc, MSc, PhD (senior clinical embryologist).

Klinefelter syndrome or 47,XXY is a genetic abnormality that occurs as a consequence of an incorrect division of homologous chromosomes during meiosis, which give raise to the gametes of one of the parents. It can also occur during the first divisions of the zygote.

Males affected by it suffer from hypogonadotropic hypogonadism, gynecomastia, learning disabilities, and infertility. It is the most common genetic disease in males. Some men, however, do not have symptoms, and they don’t know that they have this condition until they are adults and have infertility issues.

What is the lifespan of men with Klinefelter syndrome?

By Zaira Salvador BSc, MSc (embryologist).

Lifespan of males affected by KS is almost the same as the rest of the population, with perhaps a difference of 2 to 3 years.

Males with Klinefelter syndrome can have a normal lifestyle, although they have a higher chance of suffering from other health problems, such as diabetes type 2, breast cancer, and autoimmune diseases such as lupus.

Is Klinefelter syndrome associated with homosexuality?

By Zaira Salvador BSc, MSc (embryologist).

No, various studies have shown that there is no association between Klinefelter syndrome and homosexuality.

Can Klinefelter develop in females?

By Zaira Salvador BSc, MSc (embryologist).

Babies born with genotype 47,XXY are born males, that is, they have the typical physical features of males, with a penis and testicles. This is due to the presence of the Y chromosome.

Suggested for you

Azoospermia is the main cause of infertility in males affected by KS. To learn more about this sperm disorder, read: What Is Azoospermia?

If you are interested in learning about the most common causes of male infertility nowadays, check this out: What Causes Male Infertility? – Symptoms, Treatment & Statistics.

References

Abramsky L, Chapple J, 47,XXY (Klinefelter syndrome) and 47,XXY: estimated rates of and indication for postnatal diagnosis with implications for prenatal counselling, abstract Pub Med, Prenat Diagn, 1998 Mar, 18(3), pages 303-4, accessed July 2005.

Arce B, Padron S, Spermatogenesis in Klinefelter’s syndrome, abstract Pub Med, Reproduction, 1980, Apr-Jun, 4(2), pages 177-84.

Bojesen A, Juul S, Gravholt C, Prenatal and Postnatal Prevalence of Klinefelter Syndrome: A National Registry Study, The Journal of Clinical Endocrinology & Metabolism, 2003, 88(2), pages 622-26.

Delhanty, J.D.A. and Handyside, A.H. (1995) The origin of genetic defects in the human and their detection in the preimplantation embryo. Hum. Reprod. Update, 1, 201–215.

Denschlag D, Tempfer C, Kunze M, Wolff G, Keck C, Assisted reproductive techniques in patients with Klinefelter syndrome; a critical review, Fertility and Sterility, Vol 82, 4, Oct 2004, pages 775-79.

Grabski J, Pusch H, Schirren C, et al, Clinical, endocrinological, histological and chromosomal investigations on Klinefelter’s syndrome, abstract Pub med, Andrologia, 1979 May-Jun, 11(3), pages 182-96.

Griffin DK, Finch KA (2005). The genetic and cytogenetic basis of male infertility. Human Fertil;8(1);19-26

Kamichke A, Baumgardt A, Horst J, Nieschlage, Clinical and diagnostic features of patients with suspected Klinefelter syndrome, abstract Pub Med, J Androl 2003, Jan-Feb;24 (1), pages 41-8, accessed July 2005.

Krausz C, Genetic Aspects of Male Infertility, European Urological Review, 2009;3(2):93-96.

Simpson JL, de la Cruz F, Swerdloff RS, et al, Klinefelter syndrome: expanding the phenotype and identifying new research directions, abstract Pub Med, Genet Med 2003, Nov-Dec; 5(6), pages 460-8, accessed July 2005.

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Authors and contributors

 Zaira Salvador
BSc, MSc
Embryologist
Bachelor's Degree in Biotechnology from the Polytechnic University of Valencia (UPV). Embryologist specializing in Assisted Procreation, with a Master's Degree in Biotechnology of Human Assisted Reproduction from the University of Valencia (UV) and the Valencian Infertility Institute (IVI). More information
License: 3185-CV
 José Luis de Pablo
BSc, MSc, PhD
Senior Clinical Embryologist
Double Degree in Biology and Biochemistry from the University of Navarra. Master’s Degree about the Theoretical Basis and Laboratory Procedures in Assisted Reproduction from the University of Valencia (UV). Senior Clinical Embryologist from the ESHRE and ASEBIR Certification in Clinical Embryology. More than 15 years of experience as the director of IVF labs. More information