Klinefelter Syndrome

from Wikipedia, the free encyclopedia
Classification according to ICD-10
Q98.0 Klinefelter syndrome, karyotype 47, XXY
ICD-10 online (WHO version 2019)
Man with Klinefelter Syndrome

The Klinefelter syndrome , and Klinefelter Reifenstein-Albright syndrome , with 47, XXY is a congenital the most common forms chromosomal abnormalities in males and the most common cause of hypogonadism . Unlike the usual male karyotype (46, XY), people with this syndrome have an additional X chromosome in all (47, XXY) or part of the body cells ( mos 47, XXY / 46, XY). The peculiarity was first described from a scientific point of view in 1942 by the Americans Harry F. Klinefelter , Fuller Albright and EC Reifenstein. The underlying karyotype was first described in 1959 by the British geneticist Patricia A. Jacobs .

root cause

The genetic cause was recognized in 1959: A peculiarity was found in the number of sex chromosomes , in which, in addition to the usual set of chromosomes in men (46, XY), at least one other X chromosome in all ( karyotype 47, XXY) or in part of the body cells present (karyotype 46, XY / 47, XXY / = mosaic shape / in 6%). The reason for the presence of an extra X chromosome is that it long before the generation of the affected boys in the ovary of the mother or the testicles of the father in the sex cells form during meiosis at a random non-moving apart ( non-disjunction ) of the sex chromosomes came so that more than one got into the maturing egg cell or sperm cell . The mosaic shape is created by non-disjunction of the sex chromosomes during mitotic division after conception. The excess X chromosome comes from the mother in about half of the cases and from the father in the other half. Maternal age is the only evidence-based risk factor for Klinefelter syndrome: From a maternal age of 40, the risk of having a child with Klinefelter syndrome is four times higher than that of women under the age of 24.


Classic Klinefelter syndrome occurs in around 1–2 out of 1,000 male newborns. In Germany there are around 41,000–82,000 boys and men with Klinefelter's syndrome. However, it is estimated that only 25% of all people will be diagnosed with Klinefelter syndrome for life. Higher-grade X chromosomal neuploidies (e.g. 48, XXXY or 48, XXYYY polysomies ) are often referred to as variants of Klinefelter's syndrome, but their occurrence is far less common (1: 18,000-1: 100,000 male births). Compared to the classic 47, XXY form, these variants cause a more serious clinical picture.


The chromosome peculiarity can affect the cognitive (thinking) and physical development and performance of boys and men with Klinefelter's syndrome, although it cannot generally be said which symptoms develop in which form in a boy or man. Sometimes only a few symptoms are noticeable. Generally it is a question of an underactive testicle .


Boys with Klinefelter syndrome are usually developed normally at birth and look no different from other children. Occasionally, however, undescended testicles or hypospadias (malfunction of the urethra) can be indicative of Klinefelter's syndrome. However, undescended testicles and hypospadias also occur in children who do not have Klinefelter syndrome. No general statement can be made about the development of boys with Klinefelter syndrome. While some boys have inconspicuous development (a large part of those affected is undetected), a small proportion of those affected is already impaired at school (e.g. concentration problems, learning problems, reading and spelling difficulties). The boys can be calmer and more passive than other toddlers. The defiant phase can be less pronounced than with her siblings. Unspecific symptoms such as lack of drive, lack of contact, low self-confidence, mood swings up to outbursts of anger and language development disorders in combination with school problems can occur. It is not currently known why this subgroup shows such problems. For example, the paternal or maternal origin of the surplus X chromosome is discussed. Some boys also show a somewhat delayed motor development: sitting, crawling and walking are learned somewhat late; some clumsiness may be found in some boys with Klinefelter syndrome. Furthermore, growth in childhood is somewhat faster than that of peers, and adult height is on average somewhat above the average in the normal population. According to the current state of knowledge, the general intelligence of the vast majority of boys or men with Klinefelter syndrome is, if at all, only slightly below the intelligence level of their siblings. However, a partial performance weakness in the linguistic area (verbal IQ) is relatively common.

Puberty and adulthood

If left untreated, puberty can be delayed in boys with Klinefelter syndrome and more difficult than in other boys of the same age. Shyness, insecurity, a low libido and a reduced perception of one's own masculinity can lead to emotional problems and isolation. While testosterone production dwindles in many sufferers during puberty (then incompletely), a real testosterone deficiency does not occur in most of those affected until the third decade of life. Indications of a testosterone deficiency already in puberty can e.g. B. be a lack of voice break. Genital abnormalities such as a micropenis, scrotum bifidum, or hypospadias are more common in individuals with Klinefelter syndrome than in the general population, but the prevalence of these is rather low. The testicles are usually relatively small (about the size of a glass marble). Even after puberty, testicular volume does not increase. Due to the lack of testosterone, the growth plates of the bones do not close in time, so that those affected often have an above-average body height with comparatively long legs. The lack of or little beard growth can be noticed; The body hair is also usually less pronounced. People with Klinefelter syndrome are at increased risk of developing gynecomastia. The muscles are usually weaker and more fatty tissue is deposited in the hip area.

Since most of the testosterone is made in the testes, men with Klinefelter syndrome are usually low on testosterone. Testosterone is the most important male sex hormone, which plays a diverse role. It is important in sperm formation, regulates the libido (sexual appetite or sex drive), but is also of importance in completely different areas, e.g. B. for lipid metabolism, vascular function, psyche, formation of red blood cells, bone metabolism and hair growth (especially beard, chest and genital hair). A testosterone deficiency can therefore cause a wide variety of symptoms: sexual disorders (loss of libido, erectile dysfunction ), scanty beard growth, reduced muscle mass and strength, altered fat distribution pattern, gynecomastia and anemia . However, these symptoms can vary widely in people with Klinefelter syndrome. Hypogonadism tends to increase with age. Testosterone levels fall into the lower normal range in early adulthood. From the age of 25, 65–85% of those affected have clinical signs of hypogonadism.

An important consequence of the underdevelopment of the testicles is an early reduced or absent sperm production. This means that there are either too few sperm in the ejaculate ( oligospermia ) or, as in most men with Klinefelter syndrome, no sperm ( azoospermia ). Because of this, the vast majority of men with Klinefelter syndrome are infertile. Men with the mosaic type (46, XY / 47, XXY) are an exception ; they are significantly more likely to find sperm.

Studies show that Klinefelter patients also suffer from an increased risk of osteoporosis . Over 40 percent of the men examined had osteoporosis or the precursor osteopenia . One study shows that bone density is normal in childhood, but then decreases after puberty. The role of testosterone deficiency is still unclear, a direct connection between testosterone and bone density in Klinefelter patients has not yet been described, but positive connections between bone density, muscle strength (as an indirect effect of testosterone) and 25 (OH) -vitamin D. More recent studies show in fact, that additional therapy with vitamin D supplements is more important to maintain bone density than testosterone therapy alone.


Individuals with Klinefelter syndrome have an increased risk of type 2 diabetes mellitus , osteoporosis , gynecomastia , epilepsy , the occurrence of thrombosis and breast cancer compared to the general population . However, the risk of breast cancer is below the normal risk for women. Studies also suggest an increased risk of developing depression .


Physical characteristics of Klinefelter syndrome can be an above-average height or tall stature, little body hair and occasionally an enlarged mammary gland. There is usually a small testicle volume of 1–5 ml per testicle (normal values: 12–30 ml) and infertility. During puberty and adulthood, low testosterone levels with simultaneously increased levels of the pituitary hormones FSH and LH in the blood can indicate the presence of Klinefelter's syndrome. A spermogram can also be part of the further investigation. Often there is a azoospermia , rarely a oligospermia before. However, Klinefelter syndrome can only be reliably diagnosed by a chromosome analysis through the detection of an additional X chromosome. A small blood sample is sufficient as test material. To determine whether it is a mosaic shape, a chromosome analysis can also be carried out on cells in the oral mucosa. Many men with a 47, XXY chromosome set are diagnosed as part of a medical evaluation when they do not want to have children. Furthermore, the Klinefelter syndrome can be diagnosed as an incidental finding prenatally as part of an invasive prenatal diagnosis ( amniocentesis , chorionic villus sampling ).


Because Klinefelter syndrome is caused by a chromosomal aberration, causal therapy is not possible. From the beginning of puberty, the existing testosterone deficiency can be compensated for with appropriate hormone replacement therapy. Testosterone supplements are available in the form of syringes, patches, or gel. A positive effect of testosterone therapy has been described on the neurocognitive level in behavior, energy level, well-being, learning ability and verbal ability, while two other studies showed no effects of testosterone treatment. Furthermore, in men with Klinefelter's syndrome is often a lack of vitamin D before. Therefore, the vitamin D level in adolescents and adults should be checked regularly. In particular in the winter months, a vitamin D substitution should be made in consultation with the treating physician , which leads to a higher bone density. If there is gynecomastia, there is the option of a mastectomy (surgical removal of breast tissue). If children have dyslexia , difficulty concentrating or lack of drive, there is the option of support measures such as speech therapy or occupational therapy . In serious cases it can be useful to talk to the teachers in order to claim compensation for disadvantages in the school.

Infertility opportunities

The new methods of reproductive medicine , especially the so-called intracytoplasmic sperm injection (ICSI) with previous testicular sperm extraction (TESE), have meanwhile repeatedly helped men with Klinefelter's syndrome to have offspring. A smaller study found that biological children of men with Klinefelter syndrome (sperm obtained by TESE) do not have an additional X chromosome and therefore no Klinefelter syndrome. If functioning sperm cells can neither be obtained from the sperm nor using the TESE, there is no possibility of conceiving biological children. Since testosterone treatment would suppress spermatogenesis, the possibility of TESE should be discussed with the treating physician with the patient and his or her parents before starting testosterone therapy. If testosterone therapy has already started, but TESE is still desired, testosterone therapy should be paused for at least 6 months so that spermatogenesis can recover.

Role of the androgen receptor morning

The androgen receptor gene ( AR gene) is located on the X chromosome and codes for the androgen receptor to which androgens (e.g. testosterone) can bind and act. The androgen receptor plays a role in the development of male sexual characteristics through gene regulation. Androgens and androgen receptors also have other important functions in men and women, such as: B. the regulation of hair growth and sex drive. In a certain region of the AR gene, the DNA building blocks cytosine (C), adenine (A), guanine (G) are repeated several times (CAGCAGCAGCAG…). For most people, the number of CAG repeats ("repeats") in the AR gene ranges from less than 10 to about 36. The shorter this repeat range, the higher the activity of the receptor. Studies have shown that the length of this CAG repeat affects the clinical appearance of individuals with Klinefelter syndrome. In a study of 77 newly diagnosed and untreated men with Klinefelter syndrome, a higher CAG repeat number was found to be associated with higher body size, lower bone density and gynecomastia . In a similar study with 35 individuals with Klinefelter syndrome, a higher number of CAG repeats was found to be inversely correlated with penis length.

Sexual development disorders

Most people are born with 46 chromosomes. The X and Y chromosomes determine a person's sex. Most women are 46, XX and most men are 46, XY. However, some individuals have only one sex chromosome (e.g. 45, X) or have multiple sex chromosomes (e.g. 47, XXX; 47, XYY or 47, XXY etc.). In addition, some men are born as a result of a translocation of a tiny section of the sex-determining region of the Y chromosome with chromosome set 46, XX. Likewise, some women are born with chromosome set 46, XY due to mutations in the Y chromosome. Obviously there are not only 46, XX women and 46, XY men, but there are a number of chromosomal abnormalities and hormone effects that help determine gender.

The biological differences between men and women result from two processes: sex determination and differentiation. The biological process of gender determination controls whether the male or female gender differentiation path is followed. The process of biological sex differentiation (development of a specific gender) comprises many genetically regulated and hierarchical development steps. When a Y chromosome is present, early embryonic testes develop around the 10th week of pregnancy. In the absence of both a Y chromosome and the influence of a testicular determining factor (TDF), ovaries develop.

By definition, sexual development disorders are present when chromosomal, gonadal or phenotypic sex do not match. 2006 was "the sexual development disorders" agreed on the term ( English Disorders of sex development , in short DSD). A distinction is made between different forms of DSD. Klinefelter syndrome (47, XXY) is a so-called DSD with aberration of the sex chromosomes. Most men with Klinefelter syndrome identify with the male gender. However, there are also men with or without Klinefelter syndrome who are more likely to identify with the female gender. In rare cases, there are also intermediate forms of gender identity.

Psychosexual development is divided into three categories: 1. Gender identity, 2. gender role (gender-typical behavior, which is very much influenced by family and social characteristics) and 3. sexual orientation. Assigned gender dissatisfaction is more common in people with DSD. It is difficult to differentiate what is causing gender dissatisfaction in people with DSD. Possible causes include a change in gene regulation, a changed prenatal effect of androgens or a gender assignment that differs from one's own perception due to family or social influences.

Autism and ADHD

Studies showed that about 11–12 percent of people with Klinefelter syndrome were diagnosed with autism. Men with KS have previously been described as shy, socially fearful, and socially withdrawn. Bruining et al. examined 51 people with KS (6 to 19 years old) and found that 27 percent of the participants met the criteria for an autism spectrum disorder (ASD) using the "Autism Diagnostic Interview-Revised". In comparison, Tartaglia et al. Found that 5 percent of people with KS (6 to 21 years old) met the ASA criteria using the Autism Diagnostic Observation Schedule. Men with KS often have verbal difficulties that can impair social communication and, in some cases, may be associated with an increased risk of ASD. One of the leading Klinefelter researchers in the Netherlands, Sophie van Rijn, describes the difficulty of those affected in grasping non-verbal signals and interpreting them correctly.

Although boys with Klinefelter syndrome have been found to be more susceptible to attention deficit hyperactivity disorder ( ADHD) , few studies systematically examined the effects on attention and hyperactivity in boys with KS. Tartaglia, et al. reported that about a third of 57 men with KS (6 to 21 years old) met the DSM IV diagnostic criteria for ADHD. Cederlöf et al. (2013) assume a four times higher risk for schizophrenia and borderline and a six times higher risk for autism and ADHD.

Classification of scientific study results

Scientific studies examine specific characteristics (e.g. frequency of an autism spectrum disorder ) in people who have already been diagnosed with Klinefelter syndrome. It is important to understand that these percentages are not applicable to the general public of individuals with Klinefelter syndrome. These percentages therefore relate to the relatively small subgroup in whom Klinefelter syndrome has already been diagnosed. These people therefore had specific abnormalities that led to the diagnosis. However, Klinefelter syndrome is only diagnosed in approximately 25% of carriers at some point in life. Conversely, this means that 75% of people with Klinefelter syndrome will never be diagnosed. However, since study results only relate to people for whom the diagnosis has already been made, they are often biased and therefore not representative. For example, it can be assumed that an autism spectrum disorder or ADHD is less common overall than the above percentages suggest. A study would be representative if it examined individuals who were prenatally diagnosed with Klinefelter syndrome.

Scientific explanations


Men with Klinefelter syndrome are approximately 5–6 cm taller than controls. The so-called pseudoautosomal regions PAR1 and PAR2 are located in the terminal areas of the X and Y chromosomes (i.e. at the ends). Genes located in these regions escape X-inactivation and are thus expressed. In men with chromosome set 46, XY, two active copies are accordingly active, while in men with chromosome set 47, XXY three copies are active. The SHOX gene, which plays an important role in growth, lies within this pseudo-autosomal region . Men with Klinefelter syndrome thus have three active SHOX genes. This increased gene dose effect is probably responsible for the tall stature and long legs. The length of the leg seems to be further influenced by the length of the CAG repeat. The length of the CAG repeats correlated positively with arm length, arm span and leg length.

See also


  • J. Visootsak, JM Graham, Jr: Klinefelter syndrome and other sex chromosomal aneuploidies . In: Orphanet J Rare Dis. , 1, October 24, 2006, p. 42. PMID 17062147 , PMC 1634840 (free full text)
  • E. Nieschlag: Klinefelter syndrome: Most common form of hypogonadism, but often overlooked or untreated . In: Dtsch Arztebl Int. , 2013; 110 (20), pp. 347-353, doi: 10.3238 / arztebl.2013.0347
  • M. Bonomi, V. Rochira: Klinefelter syndrome (KS): genetics, clinical phenotype and hypogonadism . In: J Endocrinol Invest. , 2017; 40 (2), pp. 123-134. PMID 27644703 , PMC 5269463 (free full text)

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