2011 Group Project 3

From Embryology
Note - This page is an undergraduate science embryology student group project 2011.
2011 Projects: Turner Syndrome | DiGeorge Syndrome | Klinefelter's Syndrome | Huntington's Disease | Fragile X Syndrome | Tetralogy of Fallot | Angelman Syndrome | Friedreich's Ataxia | Williams-Beuren Syndrome | Duchenne Muscular Dystrolphy | Cleft Palate and Lip

Klinefelter's Syndrome

--Mark Hill 14:36, 8 September 2011 (EST) Good sub-heading structure and overall draft text layout. Some sections very content poor, who was working on Diagnosis and Current Research? In particular where are all the figures???

  • Introduction- you have the content there, but it reads very poorly in structure. You should try and fix this. Remember the introduction is the first thing that people will read. Also good to have some figure to interest the reader. There are also lots of clinical terms that may not be understood by the average undergraduate student.
  • History - There are only 3 worthy features in the history of this disease? You have not done the work here. This should perhaps also be structured as a timeline, bullets date first in bold.
  • Epidemiology - read the first sentence, its not English. The next section also is not very clear. I think this whole section should be looked at again in terms of structure and clarity.
  • Signs and Symptoms - this should illustrate some of these Signs and Symptoms, not the genital features please.
  • Diagnosis - OK this is sort of a description for Karyotyping, but it is not complete or accurate description of the method. Look it up please and fix this.
  • Etiology - this is not a description of non-disjunction, which is what this section should be about.
  • Pathogenesis - first sentence is repetition of previous sections, this should have been fixed by now so that the same content does not appear in multiple sub-headings.
  • Case Study- I don't think you need this section.
  • Other Similar Defects -first identify why they are similar, then explain how you will describe in a table.
  • Current Research - very poor. Who in the group should have done this section?


In normal meiosis (the process of the production of germ or sex cells) the resulting daughter cells will have only one sex chromosome, X or Y. Then, upon fertilisation, the genetic components of the two germ cells combine to form a single complete genome. This is complete with two sex chromosomes (out of 46), 46,XX for a female or 46,XY for a male. However, there a number of known abnormalities involved with the arrangement and functioning of these chromosomes. One of these is known as Klinefelter's syndrome. This describes a syndrome where a person may have one or more extra X chromosomes. This is most commonly due to a process known as non-disjunction during meiosis. [1].

Meiotic non-disjunction

In some very rare cases two or more extra copies of the X chromosome may be present (48,XXXY, or 49,XXXXY). This generally results in more emphasised clinical features typically present in Klinefelter's syndrome. In approximately 20% of cases, 46,XY/47,XXY mosaicism can occur. [2] This refers to the situation where the extra chromosome is only present in some cells, mostly due to errors occurring during mitosis.

Klinefelter's syndrome usually presents with a few standard clinical abnormalities. Affected men generally have reduced fertility and suffer from hypogonadism. However, a high proportion of affected men may not show any symptoms and the severity of the disorder differs greatly from person to person. It is suggested to be one of the most common conditions caused by non-disjunction[3]. Diagnosis is usually done by karyotyping, which allows a look at all of the chromosomes and thus identification of a chromosomal disorder. This can also be done while the fetus is in the womb. This is a huge step forward, in the past most cases were identified significantly later in life by the clinical symptoms. Early diagnosis means the implementation of treatment earlier and thus the increased potential for normal development. [4]

This disorder was first described by Harry F. Klinefelter in 1942 [5]. He described a disorder characterised by gynecomastia and a very specific type of hypogonadism, as well as an absence of spermatogenesis.

Klinefelter's syndrome is mainly managed by testosterone replacement therapy. This encourages normal development through puberty, and helps counteract some of the typical clinical symptoms of the syndrome. [6] There are also fertility treatments available that have shown mdoerate success, giving men with Klinefelter's syndrome the opportunity to reproduce. [7]

There has been significant recent research in understanding the neural developmental implications of having an extra X chromosome. [8] Klinefelter's syndrome has even been used as a model to further understand development and the role the X chromosome plays. With the increased use of animal models, much has been revealed about the syndrome that was not previously known. [9]


Klinefelter syndrome was first described by Harry F. Klinefelter and his colleagues in 1942. Their observations of nine patients where characterised by a number of peculiar symptoms; gynecomastia (breast development), azoospermia, hyalinised and small testes, absent spermatogenesis, elevated levels of follicle-stimulating hormone (FSH) and hypogonadism. [10] [11]

In 1949, Murray L. Barr and Ewart G. Bertram discovered that patients with Klinefelter’s syndrome had positive sex chromatin material in their epithelial cells, this is normal for females but not in males. [12] It was a dense chromatin mass which they later termed, Barr body. This discovery led to the use of smears of stained buccal mucosal cells which determined whether the infant’s genetic sex matched the phenotypic sex.

The late 1950’s led to a breakthrough in understanding Klinefelter’s syndrome. In 1956, investigations described 7 patients with Klinefelter’s syndrome as a result of the buccal smears that demonstrated Barr bodies (2). However, the cause of the syndrome remained unknown until 1959, when a discovery that a patient with KS had 47 chromosomes, including an extra X chromosome established that the Barr body seen in patients with KS corresponds to an extra X chromosome. [13]


The emotional response and comprehension of men with Klinefelter’s Syndrome differs from that of normal men
The average intellect of boys with Klinefelter's Syndrome differs from that of normal males

One of the most common disorders of sex chromosomes in humans is Klinefelter’s syndrome, otherwise known as 47,XXY gene mutations. This is prevalent in around 1 in 500 males[14]. There can also be variations of this genetic condition, and these variations are referred to as chromosomal aneuploidies.

The chromosomal variations are present within 1 in 50 000 male births, so are much rarer than 47,XXY mutations. It is said that males born with Klinefelter’s syndrome often go through life without being karyotyped, meaning that they are left undiagnosed[15]. Males born with Klinefelter syndrome often fail to produce sperm, and have very low testosterone levels due to largely to them having small testes. They have increased susceptibility to diabetes, cardiovascular disease and cancer, although it is still unclear why.

In around 80% of cases, the karyotype for Klinefelter’s syndrome is shown in every cell of the body. The age of the mother and father at the time of conceiving a child has no relation at all to whether a child will be born with the condition. The appearance or phenotype of Klinefelter syndrome often becomes evident after puberty. Prior to puberty, the pituitary gland and gonad function is relatively normal in sufferers[16]. Males with Klinefelter’s syndrome generally have IQs which are 10-15 points lower than the general population. Interestingly, these differences in IQ levels were only minor. There is also a decreased head circumference found in XXY males as opposed to normal karyotype males. As well, males with Klinefelter’s syndrome generally have delayed speech development[17]. There is also a higher chance that those affected will experience behavioural problems, possibly due to lower IQ levels.

The vast majority of males are not diagnosed prenatally with Klinefelter’s syndrome. A typical male suffering from Klinefelter’s is characterized by abnormally long legs and arm span, feminine-like distribution of adipose tissue including a condition known as gynecomastia, absent or decreased facial and pubic hair as well as small hyalinized testes and a small penis [18]. There has also been an association hypothesized between tooth size and Klinefelter's syndrome[19]. This could be attributed to a growth gene which may be found in the Y chromosome, as opposed to the X chromosome since females have a smaller crown size than males. Since 47,XXY males have a taller body stature than normal males, it is not a surprise that Klinefelter sufferers have larger tooth sizes.

Seizures can typically occur, and when seizures occur in males with Klinefelter's syndrome, it usually happens between 3 months and 3 years of age. Neuro-imaging tests have failed to identify the cause of the seizures[20]. It is very difficult to diagnose a child with Klinefelter's syndrome immediately, since many of the symptoms that are exhibited in childhood may be due to other factors, such as shyness, stress, and social phobia. Across are two graphs adapted from recent studies which demonstrate both the emotional response to stimuli of men with Klinefelter's syndrome, and the intelligence of males with Klinefelter's syndrome compared to normal males.

Signs and Symptoms

Screening is recommended when the following signs of Klinefelter syndrome are observed.

• Infertility

• Delayed speech and language development

• Accelerated growth in height

• Subnormal intelligence or mental retardation (severity is proportional to the number of extra X chromosomes)

• Behavioral problems or psychological distress

These are the symptoms.

• Small, firm testes

• Small penis

• Decreased pubic, facial and armpit hair

• Enlarged breast

• Tall physique

• Abnormal body proportions (long limbs and short trunk)

[21] [22]


Karyotype of leukocytes can be done to diagnosis this condition. Karyotype is a procedure where a sample of blood taken. Leukocytes (white blood cells) are separated from the sample and cultured onto a tissue medium. The chromosomes of these cells are then analyzed for aberrations, additional X chromosomes.



The additional sex chromosome in men with Klinefelter syndrome results from non-disjunction and may result from either a paternal or maternal origin. Klinefelter syndrome usually encompasses the clinical consequences of an XXY karotype. There are other variant karotypes which can occur that can include an additional X chromosome or an additional X and Y chromosome. Men with these karotypes often have often more severe phenotypes with those of the XXY karotype. (1)

The additional X chromosome in 47, XXY results sporadically from either meiotic or mitotic non-disjunction in the developing zygote. The possibility of X chromosome non-disjunction increases with advancing maternal age. Each additional X chromosome is associated with an IQ decrease of 15-16 points (2). The physical manifestations of Klinefelter syndrome are predominantly moderate, as the additional X chromosome is usually inactivated. However, the X chromosome is not completely inactivated. As the number of X chromosome increases the phenotypes are more severe (1).

48, XXYY are thought to result from the fertilisation of a normal female oocyte with an aneuploid sperm produced through nondisjunction events in both meiosis 1 and 2 spermatogenesis. With 47, XXY postzygotic nondisjunction may occur in mitosis in 8% of individuals with XXY and 14% with XXX.

  • Mosaicism occurs in generally 15% of men, with an additional X chromosome.
  • Developmental and behavioural phenotypes


An additional X chromosome in a Klinefelter syndrome patient is acquired through abnormal cellular division. More often the aberrant cell division results when the event of nondisjunction takes place during parental gametogenesis. This is where the homologous chromosome or sister chromatid has failed to separate normally thus making the distribution of genetic content amongst the daughter cell uneven. So the sperm or the egg not only has the normal single sex chromosome but also an extra X chromosome. Apart from nondisjunction, uneven separation during mitosis in the zygote can lead to an extra X chromosome.

As a result of this genetic mutation, the characteristic shrunken testes and the absence of motile sperm of the Klinefelter syndrome can be observed. These symptoms indicate that the seminiferous tubule and sertoli cells have lost its function. This has many consequences, one of which is the decreased inhibin hormone level. This in turn results in the elevation of gonadotropin level, which is the hallmark of Klinefelter syndrome.

Gonadotropin levels increases as a result of low levels of inhibin because it act as a feedback inhibitor on the pituitary gland. However, the elevated gonadotropin level can only be observed during and after puberty. This is shown in a study with prepubertal boys. One group of subjects have an additional X chromosome while the control group did not. By comparing the two groups a difference in the gonadotropin level was not observed.



Androgen Therapy

Androgen therapy involves the replacement of testosterone. This is primarily given to stimulate the onset of puberty in affected males. Ideally, testosterone is given from the age that puberty usually occurs, in order to encourage normal development. In addition to this, it assists in treating or preventing some of the more typical clinical presentations of this disorder. Testosterone replacement encourages secondary sexual attributes, and helps ensure standard bone and muscle mass[25].

Samango-Sprouse et al found that the initiation of androgen therapy early in life was highly associated with improvments in speech and cognition, and other neurogical development. This research was based around children with severe Klinefelter's syndrome - 49,XXXXY. This gives much hope to the prospect of early treatment resulting in normal development of those afflicted with Klinefelter's syndrome. [26]

However, it has also been associated with a decrease in fertility, especially if given early in life. Premature treatment has been suggested to result in delayed puberty and abnormal physical development during this period[27]. It is also recommended to stop testosterone replacement a few months prior to the administration of infertility treatment[28].


Aromatase inhibitors can be administered to men, in order to lower intratesticular estradiol levels. This is thought to encourage the production of testosterone and activate spermatogenesis[29]. There are two main methods used to treat non-obstructive azoospermia, microdissection testicular sperm extraction (TESE) and conventional TESE. These are methods of extracting what sperm is present in the testes for use in in vitro fertilisation (IVF). It has been shown that microdissection TESE has a higher rate of extraction, and allows for minial testicular damage[30], and so conventional TESE is slowly being replaced by microdissection TESE. The most common IVF technique used in these situations is intracytoplasmic sperm injection, where a single sperm is injected into a single oocyte. This means that for the highest chance of success, the extraction of both the sperm and the egg need to be well timed[31]. Before surgery, men are usually administered aromatase inhibitors for a few months. This is to restore the ratio of testoserone to esradiol back to normal levels, and to encourage the amount of viable sperm present. [32][33]

Other Similar Defects

Abnormality Description Similarities Differences Image
Turner Syndrome (XO) This is a condition where a female only has one sex chromosome (45,XO). Girls with Turner syndrome lack certain characteristics, such as full grown ovaries, metabolic problems, short stature and decreased life expectancy [34].

In embryology, the embryo may present with a web-like neck, low birth length and lymphedema of the dorsum of hands and feet. There may also be a delay in puberty because of gonadal dysgenesis. As well as all this, there may also be congenital defects of the heart, kidney and autoimmune system [35].

  • Abnormal karyotype
  • People are also generally infertile
  • The phenotype of is very variable, in that girls may present with the standard symptoms from it as aforementioned, or they may be asymptomatic and blend in with the rest of the population
  • People with Klinefelter’s and Turners may both have learning difficulties, and difficulties with social interaction [36]
  • Results from the loss of a chromosome, as opposed to the addition of a chromosome
  • Many females with Turner’s syndrome have normal intelligence, whereas males with Klinefelter’s syndrome tend to have slightly below average intelligence
Immunoglobulin levels in 15 Turner girls. The shaded boxes indicate the 95% confidence interval for the 5–20 years age group. Girls with recurrent otitis media are illustrated with open symbols (n = 8) and those who are otitis free with filled symbols (n = 7)
47,XYY This is a condition where a male inherits an extra Y chromosome. The additional Y chromosome is from the father (paternal origin) and there is existing evidence that spermatocytes with additional Y chromosomes are selected against during gametogenesis [37]. This condition only affects males.

This condition is not usually passed on from parents to offspring, and it has been shown that the sperm of 47,XYY males has the normal karyotype [38].

  • Results from the addition of a chromosome
  • Boys have an increased risk of having learning difficulties which could begin in their early childhood
  • Boys with 47,XYY may have a slightly lower IQ than their peers
  • The condition is completely asymptomatic in most cases, this is the reason for the debate regarding whether it should be termed a ‘syndrome’
  • Boys with 47,XYY Syndrome are fertile and produce normal testosterone levels
  • Boys with 47,XYY syndrome tend to have some impairment in language development, albeit minor, whereas boys with Klinefelter’s syndrome have some form of motor impairment function [39]
Karyogram of male with 47,XYY Syndrome
48,XXYY 48,XXYY, frequently referred to as another variant of Klinefelter’s syndrome, is an anomaly whereby males have an extra X and Y chromosome. Sometimes, renal clearance can be affected by this condition. This is caused by low levels of serum urate in conjunction with high levels of renal urate clearance [40].
  • The physical phenotype of the condition is very similar to Klinefelter’s Syndrome, since males have a tall stature, have learning disabilities and are infertile [41]
  • In some cases, signs of acromegaly have been seen in some patients with this variant, as demonstrated in a study of a 24 year old male living in Japan [42]
Male with 48,XXYY Syndrome

Current Research

Neural systems for social cognition in Klinefelter syndrome (47,XXY): evidence from fMRI; 2011

It is suggested that the addition of an X chromosome has a significant impact on neural systems. The X chromosome contains a large number of genes responsible for neural system development, and so Klinefelter's syndrome was the ideal model for the observation of neural development abnormalities. van Rijn et al used fMRI (functional magnetic resonance imaging) to observe the activity in specfic parts of the brain. People with Klinefelter's syndrome are generally socially disadvantaged, and so a link was investigated between neural activity and social cues.

It was found that Klinefelter's syndrome can be associated with decreased activity in specific neural systems. This also advocates the possibility of using Klinefelter's syndrome as a model for further study of the X chromosome. [43]

Insights into the pathogenesis of XXY phenotype from comparison of the clinical syndrome with an experimental XXY mouse model; 2010

Even after all we now know about Klinefelter's syndrome, a lot still remains a mystery. This is particularly due to the absence of a commonly used animal model. Lue et al investigated the ultimate similarities of a mouse 41,XXY model (as opposed to the human 47,XXY), and it's use in further research. It is important to have an animal model that largely resembles the human syndrome or disease. Lue et al used this model to compare phenotypic similaries between the two, in regards to hormonal imbalances and effect of additional X chromosome genes.

By the comparison of the animal model and human representative, they found that clinical symptoms and phenotype typical in Klinefelter's syndrome are likely due to an avoidance of the inactivation of the X chromosome. [44]

Expression of selected genes escaping from X inactivation in the 41, XXY* mouse model for Klinefelter’s syndrome; 2010

It still remains a debate as to the exact molecular and genetic actions that result in the presentation of Klinefelter's syndrome. It has been suggested that some of the genes on the X chromosome escape inactivation and so result in the clinical symptoms of Klinefelter's syndrome. Werler et al explored this theory using two mouse models (41,XXY and 41,XXY*) and epigenetics. Out of the genes that were obseved in this study, they all seemed to undergo escape from X chromosome inactivation similarly to female mice.

There were also noticable tissue differences, wherein gene expression in the brain was significantly different the liver and kidney. In the brain there was substantial upregulation of these "X-linked excapee genes". This is suggested to directly affect the phenotypic presentation of 47,XXY syndrome. [45]



Acromegaly -

Androgen -

Aneuploidies - Abnormal number of chromosomes

Azoospermia - Occurs when males have little to no sperm in the semen


Barr bodies - Inactivated X chromosome in females due to sex being determined by W or Y chromosomes instead of XY

Buccal mucosal cells - Cells that secrete mucus


Chromatin - Composed of genetic material that forms chromosomes and is com posed of DNA


Dysgenesis - Defective or abnormal development of an organ, especially of the gonads


Gametogenesis - Biological process by which haploid or diploid cells undergo division and/or differentiation to form mature haploid gametes.

Gonadotropin - Protein hormones secreted by gonadotrope cells of the pituitary gland.

Gynecomastia - Is the abnormal development of large mammary glands in males which give large breasts.


Hyalinised - The state of something being hyaline (clear and translucent)

Hypogonadism - Occurs when the sex glands produce little to no hormones.


In vitro fertilisation -


Karyotype - Number and/or appearances of chromosomes in a eukaryotic cell nucleus


Leukocytes - White blood cells which are cells of the immune system


Meiosis -

Mosaicism -


Non-disjunction -


Pituitary gland - Endocrine gland that secretes hormones that regulate homeostasis

Post zygotic non-disjunction -


Seminiferous tubule - Long, thread like tubes found in the testes and are the specific location of meiosis in the body.

Sertoli cells - Cell of the testes that is part of the seminiferous tubule. It is activated by Follicle Stimulating Hormone

Spermatogenesis - Process by which male germ cells undergo division and produce a number of cells referred to as spermatogonia, through which spermatocytes are derived from.


X and Y chromosomes - X chromosomes come from the female and code for some female characteristics. Y chromosomes come from the male and code for male characteristics. XX is for a female and XY is for a male.


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2011 Projects: Turner Syndrome | DiGeorge Syndrome | Klinefelter's Syndrome | Huntington's Disease | Fragile X Syndrome | Tetralogy of Fallot | Angelman Syndrome | Friedreich's Ataxia | Williams-Beuren Syndrome | Duchenne Muscular Dystrolphy | Cleft Palate and Lip