Difference between revisions of "2011 Group Project 3"

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='''Klinefelter's Syndrome'''=
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__TOC__
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==Introduction==
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[[File:47,XXY Klinefelter's Syndrome.jpg|thumb|right|260px|Figure 1: 47,XXY Klinefelter's Syndrome]]
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Klinefelter's syndrome, first described in 1942 by Harry F. Klinefelter<ref>Klinefelter HF, Reifenstein EC & Albright F. '''Syndrome characterized by [[#Glossary | '''gynecomastia''']], aspermatogenesis without a-Leydigism, and increased excretion of follicle-stimulating hormone.''' American Journal of Clinical Dermatology 1942; 2: 615–627.</ref>, is caused by the addition of one or more X chromosome(s) in affected males .  He depicted a disorder characterised by [[#Glossary | '''gynecomastia''']] and a very specific type of [[#Glossary | '''hypogonadism''']], as well as an absence of [[#Glossary | '''spermatogenesis''']].
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It is still largely associated with these defects, the most common including reduced fertility and [[#Glossary | '''hypogonadism''']].  A high proportion of affected men may remain asymptomatic their whole lives, this is because the severity of the disorder differs greatly from person to person<ref name="kline">Wikström AM, Dunkel L. '''Klinefelter syndrome'''. Best Pract Res Clin Endocrinol Metab: 2011, 25(2):239-50</ref>.
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The extra chromosome present is largely due to a genetic abnormality known as [[#Glossary | '''non-disjunction''']] that can occur during either mitosis or [[#Glossary | '''meiosis''']], this is described in more detail below and portrayed in [[Media: 47,XXY Klinefelter's Syndrome.jpg|Figure 1]].  It has also been suggested to be the most common disorder associated with [[#Glossary | '''non-disjunction''']] <ref name="kline"/>
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There are a number of diagnostic techniques currently used to determine accurate and early identification of the syndrome.  This is particularly useful to encourage the implementation of the best treatment plan to manage the symptoms of the syndrome<ref><pubmed>20392711</pubmed></ref>.  The phenotype of the syndrome differs significantly through the different stages of life, and a particular stage will correspond to the best management protocol for that point.
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=Klinefelter's Syndrome=
 
  
--[[User:S8600021|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.
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* 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.
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==History==
* 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.
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[[File:Steps in a classic array CGH-analysis used for the most common chromosomal abnormalities.png|thumb|right|250px| Figure 2: Steps in a classic array CGH-analysis used for the most common chromosomal abnormalities]]
* Signs and Symptoms - this should illustrate some of these Signs and Symptoms, not the genital features please.
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Klinefelter syndrome (KS) 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; [[#Glossary | '''gynecomastia''']], [[#Glossary |'''azoospermia''']], hyalinised and small testes, absent [[#Glossary|'''spermatogenesis''']], elevated levels of follicle-stimulating hormone (FSH) and [[#Glossary| '''hypogonadism''']]<ref name="PMID17415352"><pubmed>17415352</pubmed></ref> <ref name="kline"/>
* 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.
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* Etiology - this is not a description of non-disjunction, which is what this section should be about.
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In 1956, an investigation was carried out with 7 patients with KS that had the buccal smears that demonstrated Barr bodies . However, the cause of the syndrome remained unknown until 1959, when Jacobs and Strong discovered that a patient with KS had 47 chromosomes, including an extra X chromosome in the karotype of the patient <ref name="PMID17415352"/>. As recorded in their article 'A case of human intersexuality having a possible XXY sex-determining mechanism';
* 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.
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* Case Study- I don't think you need this section.
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* Other Similar Defects -first identify why they are similar, then explain how you will describe in a table.
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{| align="center"| style="border"
* Current Research - very poor. Who in the group should have done this section?
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|- align="center" | bgcolor = "DDCEF2"
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|''“…There are strong grounds, both observational and genetic, for believing that human beings with chromatin-positive nuclei are genetic females having two X chromosomes. The fact that this patient is chromatin-positive and has an additional chromosome within the same size range as the X, as well as an apparently normal Y, makes it seem likely that he has the genetic constitution XXY”''<ref name="PMID13632697"><pubmed>13632697</pubmed></ref>
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|}
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This discovery confirmed that the Barr bodies seen in patients with KS corresponds to an extra X chromosome<ref name="PMID13632697"/>. In 1966, Harry F. Klinefelter reported that the extra X chromosome results from either meiotic [[#Glossary | '''nondisjunction''']] or [[#Glossary | '''anaphase lag''']]<ref name="PMID3529433"><pubmed>3529433</pubmed></ref>.  
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The ‘prototypic’ man with KS was initially described as tall, with narrow shoulders, broad hips, sparse body hair, gynecomastia, small testes, [[#Glossary | '''androgen''']] deficiency and reduced verbal intelligence<ref name="PMID17415352"/>. However, a few years after the syndrome was described Heller and Nelson reported that the gynacomastia was not a necessary part of the syndrome, even though it occurred in about 75% of the patients which they observed. The hallmarks of the syndrome were then thought small testes, sterility and increased excretion of follicle stimulating hormone<ref name="PMID3529433"/>. Extensive studies of these patients during their adolescence illustrated the various personality traits, which can be handled by proper counselling. Similar to today, Harry Klinefelter reported that most patients with this condition were not diagnosed until early adult life, when counselling may be less rewarding.  
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Below is a timeline highlighting all the major advancements and developments in KS.  
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==Introduction==
 
  
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.
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===Timeline===
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. <ref><pubmed>17062147</pubmed></ref>. 
 
  
[[File:Meiotic non-disjunction.jpg|right|300px|Meiotic non-disjunction|thumb]]
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{| style="border: solid 1px #a0a0ff"
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|- align="center"
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|-bgcolor="DDCEF2"
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|style="width:50px"|'''Year'''
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| '''Discovery'''
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|-
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| valign="top" bgcolor="DDCEF2"|'''1942'''
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| valign="top" bgcolor="lightyellow" | Dr. Harry Klinefelter and his co-workers at Massachusetts General Hospital in Boston published a report on 9 men describing the signs and symptoms of KS. The ‘prototypic’ man with KS was described as tall, with narrow shoulders, broad hips, sparse body hair, gynecomastia, small testes, androgen deficiency and reduced intelligence. <ref name= "PMID17415352"/>
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|-
  
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. <ref><pubmed>21397196</pubmed></ref>  This refers to the situation where the extra chromosome is only present in ''some'' cells, mostly due to errors occurring during mitosis.
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| valign="top" bgcolor="DDCEF2"|'''1949'''
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| valign="top" bgcolor="lightyellow" | Barr and Bertram noticed positive [[#Glossary | '''chromatin''']] material in KS patients.It was a dense chromatin mass which they later termed, Barr body.
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|-
  
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| valign="top" bgcolor="DDCEF2"|'''1956'''
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| valign="top" bgcolor="lightyellow" | The discovery of [[#Glossary | '''Barr bodies''']] as a result of the new development of Buccal smears
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|-
  
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<ref><pubmed>17062147</pubmed></ref>.  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. <ref><pubmed>20392711</pubmed></ref>
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| valign="top" bgcolor="DDCEF2"|'''1959'''
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| valign="top" bgcolor="lightyellow" | Jacobs and Strong discovered that it was a chromosomal disorder, with the appearance of an extra X chromosome.
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|-
  
This disorder was first described by Harry F. Klinefelter in 1942 <ref>Klinefelter HF, Reifenstein EC & Albright F. '''Syndrome characterized by gynecomastia, aspermatogenesis without a-Leydigism, and increased excretion of follicle-stimulating hormone.''' American Journal of Clinical Dermatology 1942; 2: 615–627.</ref>.  He described a disorder characterised by gynecomastia and a very specific type of hypogonadism, as well as an absence of spermatogenesis.
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| valign="top" bgcolor="DDCEF2"|'''1960s'''
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| valign="top" bgcolor="lightyellow" | Development of chromosome banding techniques. <ref><pubmed>5640698</pubmed></ref>  
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|-
  
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| valign="top" bgcolor="DDCEF2"|'''1962'''
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| valign="top" bgcolor="lightyellow" | Maclean and Mitchell’s studies on inmates in prisons and institutions for mental health revealed an increased risk of psychiatric disorders, mental retardations and criminal behaviour in patients with KS. <ref name="PMID17415352"/>
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|-
  
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. <ref><pubmed>20482304</pubmed></ref>  There are also fertility treatments available that have shown mdoerate success, giving men with Klinefelter's syndrome the opportunity to reproduce. <ref><pubmed>21811543</pubmed></ref>
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| valign="top" bgcolor="DDCEF2"|'''1966'''
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| valign="top" bgcolor="lightyellow" |Dr. Harry Klinefelter reports that the extra X chromosome results from either meiotic [[#Glossary |'''non-disjunction''']] or anaphase lag. <ref name="PMID3529433"/>
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|-
  
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| valign="top" bgcolor="DDCEF2"|'''1970'''
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| valign="top" bgcolor="lightyellow" | Rozen et al reported that approximately 1% of all individuals institutionalised with mental retardation have an XXY karotype. <ref><pubmed>4398603</pubmed></ref>
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|-
  
There has been significant recent research in understanding the neural developmental implications of having an extra X chromosome. <ref><pubmed>21737434</pubmed></ref>  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. <ref><pubmed>21217605</pubmed></ref>
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| valign="top" bgcolor="DDCEF2"|'''1970s'''
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| valign="top" bgcolor="lightyellow"| A number of centres began screening newborns for sex [[#Glossary | '''chromatin''']] abnormalities.
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|-
  
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| valign="top" bgcolor="DDCEF2"|'''1986'''
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| valign="top" bgcolor="lightyellow"| Dr. Harry Klinefelter described that the hallmarks of the syndrome are now small testes, sterility and increased excretion of follicle stimulating hormone. <ref name="PMID3529433"/>
  
==History==
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He also reported that most patients with this condition were not diagnosed until early adult life, when counselling may be less rewarding. <ref name="PMID3529433"/>
  
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. <ref><pubmed> 17415352 </pubmed></ref> <ref><pubmed> 21397196 </pubmed></ref> 
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Treated hypogonadism with injected testosterone, and thought this also aided personality abnormalities in adolescent patients. <ref name="PMID3529433"/>
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|-
  
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| valign="top" bgcolor="DDCEF2"|'''1992'''
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| valign="top" bgcolor="lightyellow"| The Comparative Genomic Hybridization (CGH) analysis was developed as a genome wide screening strategy for detecting DNA copy number imbalances.<ref><pubmed> 1359641</pubmed></ref>  A classic array-CGH experiment is shown in [[Media:Steps in a classic array CGH-analysis used for the most common chromosomal abnormalities.png|Figure 2]].
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|-
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| valign="top" bgcolor="DDCEF2"|'''1995'''
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| valign="top" bgcolor="lightyellow"| Reiss et al., found that half all mental retardation in males originates from a defective gene on the X chromosome. Thus, the X chromosome comprises the genes involved in human cognition. <ref><pubmed>7585014</pubmed></ref>
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|-
  
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. <ref><pubmed> 15729733</pubmed></ref>   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.
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| valign="top" bgcolor="DDCEF2"|'''1998'''
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| valign="top" bgcolor="lightyellow"| Smyth and Bremmer concluded that XXY karotypes occurs in 1 in 500 live male births and is the most common type of human chromosome anomaly. <ref><pubmed>9645824</pubmed></ref>
  
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They also hypothesised that the characteristics features of KS originate from genes escape inactivation and are expressed in excess.
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|-
  
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. <ref><pubmed> 13632697</pubmed></ref>
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| valign="top" bgcolor="DDCEF2"|'''2002'''
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| valign="top" bgcolor="lightyellow"| Crow et al., suggested that at least one gene or genes in the X-Y homologous regions of the sex chromosomes which escape’s normal X- inactivation are crucial for language functioning.<ref><pubmed> 15729733</pubmed></ref>
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|-
  
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| valign="top" bgcolor="DDCEF2"|'''2010'''
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| valign="top" bgcolor="lightyellow"| Stefano Gambardella et al., designed a targeted array called GOLD (gain or loss detection) Chip which detects unexpected major chromosome imbalances. <ref>Stefano G., Erika C., Francesca M., Giusy S., Francesca G., Michela B., Anna M. N., Antonio N., Ercole B., Laura B. and Giuseppe N.(2010) Design, Construction and Validation of Targeted BAC Array-Based CGH Test for Detecting the Most Commons Chromosomal Abnormalities. ‘’Genomic Insights.’’ 3:9-21</ref>
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|-
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|}
  
 
==Epidemiology==
 
==Epidemiology==
  
[[File:Processing of social cues in both normal men and men with Klinefelter's Syndrome.jpg|thumb|right|The emotional response and comprehension of men with Klinefelter’s Syndrome differs from that of normal men]]
 
  
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<ref><pubmed>17062147</pubmed></ref>. 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<ref><pubmed>9160389</pubmed></ref>. 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.  
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One of the most common disorders of sex chromosomes in humans is Klinefelter’s syndrome (KS), otherwise known as 47,XXY gene mutations. This is prevalent in around 1 in 500 males<ref name="PMID17062147"><pubmed>17062147</pubmed></ref>. There can also be variations of this genetic condition, and these variations are referred to as chromosomal aneuploidies.
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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 KS often go through life without being [[#Glossary | '''karyotyped''']], meaning that they are left undiagnosed<ref><pubmed>9160389</pubmed></ref>. In around 80% of cases, the [[#Glossary | '''karyotype''']] for KS 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.
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A link was found between increased risk of mortality and KS.  There was “a significant increase in mortality risk of 40% (hazard ratio, 1.40; 95% confidence interval, 1.13–1.74), corresponding to a significantly reduced median survival of 2.1 yrs.’’ <ref name="PMID15292313"><pubmed>15292313</pubmed></ref >The increased mortality was because of infections, neurological, circulatory, pulmonary, and urinary tract diseases which people with KS are more susceptible too. There are studies currently being conducted into whether socioeconomic background increases the risk of a child developing KS<ref name="PMID15292313"><pubmed>15292313</pubmed></ref>.
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Seizures can typically occur, and when seizures occur in males with KS, it usually happens between 3 months and 3 years of age. Neuro-imaging tests have failed to identify the cause of the seizures<ref name="PMID20438626"><pubmed>20438626</pubmed></ref>. It is very difficult to diagnose a child with KS immediately, since many of the symptoms that are exhibited in childhood may be due to other factors, such as shyness, stress, and social phobia. [[Media: Processing of social cues in both normal men and men with Klinefelter's Syndrome.jpg|Figure 3]] is a graph adapted from recent studies, demonstrating the emotional response to stimuli of men with KS compared to normal males. It has also been suggested that men with KS are 50% more at risk of being diagnosed with breast cancer, as shown in [[Media: Risk factors for male breast cancer.JPG|Figure 4]].<ref><pubmed>20463819</pubmed></ref>
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<gallery widths="240px" heights="190px" align="center" perrow="2">
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File:Processing of social cues in both normal men and men with Klinefelter's Syndrome.jpg|Figure 3: The emotional response and comprehension of men with Klinefelter’s Syndrome differs from that of normal men
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File:Risk factors for male breast cancer.JPG|Figure 4: Risk factors associated with male breast cancer
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</gallery>
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==Aetiology==
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Chromosome abnormalities have a high incidence in humans. The most common type is [[#Glossary | '''aneuploidy''']], which is the loss (monosomy) or gain (trisomy) of an entire chromosome <ref name="PMID12926525"><pubmed>12926525</pubmed></ref>. [[#Glossary | '''Aneuploidy''']]’s occur in approximately 5% of pregnancies which survive long enough to be seen and approximately 10-25% of all fertilised human oocytes are either monosomic or trisomic <ref name="PMID12926525"/>. Trisomies are incapable of normal development, the consequences are less severe for the sex chromosomes than the autosomes, leading to enhanced sex chromosomes among live-borns in comparison with autosomal trisomies.  Abnormal chromosome distribution, is the result of one of two mechanisms; [[#Glossary | '''non-disjunction''']] and anaphase lagging. However, Klinefelter’s syndrome(KS) is more commonly caused by [[#Glossary | '''non-disjunction''']].<ref>Cynthia M. Smyth, William J. B. '''Klinefelter Syndrome''' Arch Intern Med. 1998;158:1309-1314</ref>
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===Non-Disjunction===
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[[File:Maternal Non-Disjunction.PNG |thumb|right|500px|Figure 5:Maternal Non-disjunction.]]
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[[#Glossary | '''Non-disjunction''']] is the failure of chromosome pairs to separate during the first and second meiotic divisions, as shown in [[Media:Meiotic non-disjunction.jpg|Figure 5]]. Maternal XXY can be caused by [[#Glossary | '''non-disjunction''']] during the first and second meiotic divisions, however, XXY of paternal origin can only occur during the first meiotic division. In the great majority of trisomies the additional chromosome is of maternal origin and results from an error during the first meiotic division as seen in [[Media: Maternal Non-Disjunction.PNG |Figure 5]]. However, the 47,XXY has been extensively studied and there is a 50-60% chance of it being from a paternal origin and 40-50% from a maternal origin<ref name="PMID11426451"><pubmed>11426451</pubmed></ref>. The nature of the errors by which maternal and paternal XXYs can arise are extremely diverse. Studies have established that increased maternal age has adverse affects on pregnancy and an increased chance of anueploidy.<ref><pubmed>11582569</pubmed></ref>  The process of [[#Glossary | '''meiosis''']] serves to generate haploid gametes through a specialised cell division process, consisting of two stages of cell division, MI and MII. During prophase of MI the pairs of homologous chromosomes synapse and undergo recombination, with chiasmata being formed at the sites of exchange. Their purpose is to link together the homologues and therefore play a crucial role in the proper disjunction of chromosomes in the first meiotic division <ref name="PMID12926525"/>.
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This more common aberrant cell division takes place during [[#Glossary | '''gametogenesis''']]. More specifically, it is the event of the homologous chromosome or sister chromatid failing to separate normally.<ref name="PMID17415352"/> So like anaphase lagging, the distribution of genetic content in the daughter cells is uneven. In addition, it can also occur in both of the meiotic divisions, leading to variants of KS with a greater number of X chromosomes. Some examples of these variants are 48,XXXY and 48,XXXXY. Furthermore, [[#Glossary | '''non-disjunction''']] can also take place in postzygotic division. <ref>Bandmann, H. J., Breit, R., & Perwein, E., (1984). '''Genetics and Cytogenetics of Klinefelter's Syndrome: [[#Glossary | '''Karyotype''']] of Klinefelter's Syndrome and Its Variants.''' In H. J. Bandmann, B. Reinhardt, & E. Perwein, Klinefelter's Syndrome (1, pp. 1-229). New York, America: Springer-Verlag.</ref>
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As depicted in [[Media: Nondisjunction of Homologous Chromosomes in Meiosis1.jpg| Figure 7]], when [[#Glossary | '''non-disjunction''']] takes place in the first meiotic division, a homologous pair of chromosomes is not separated in the anaphase 1. The result is one daughter cell having three chromosomes while the other has only one by the end of [[#Glossary | '''meiosis''']] -1. The daughter cell with one chromosome is not viable. When the daughter cell with three chromosomes is followed through [[#Glossary | '''meiosis''']] two, its own progeny can be seen to include either a parental and maternal X chromosome or two copies of the maternal X chromosome.
  
[[File:Age and intellectual functioning of boys with Klinefelter Syndrome and normal males.png|thumb|left|The average intellect of boys with Klinefelter's Syndrome differs from that of normal males]]
 
  
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<ref><pubmed>21397196</pubmed></ref>. 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<ref><pubmed>7065696</pubmed></ref>. There is also a higher chance that those affected will experience behavioural problems, possibly due to lower IQ levels.  
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However, if [[#Glossary | '''non-disjunction''']] occurs in the second meiotic division, then the abnormal separation of genetic material takes place in anaphase 2. This is seen in [[Media: Nondisjunction of Sister Chromatids in Meiosis 2.jpg| Figure 8]]. By the end of the second [[#Glossary | '''meiosis''']] one daughter cell contains both sister chromatids of the maternal X chromosome, while the other daughter cell does not contain that maternal genetic material.
  
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 <ref><pubmed>12574191</pubmed></ref>. There has also been an association hypothesized between tooth size and Klinefelter's syndrome<ref><pubmed>1686171</pubmed></ref>. 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.  
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The consequence of [[#Glossary | '''non-disjunction''']] is that an XX ovum or a XY sperm will be produced. This gamete will then go on to be fertilised by a normal Y sperm or an X ovum respectively and conclusively produce a XXY zygote, which is the hallmark of KS.
  
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<ref><pubmed>20438626</pubmed></ref>. 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.
 
  
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[http://www.biostudio.com/d_%20Meiotic%20Nondisjunction%20Meiosis%20I.htm Animation Meiotic Non-disjunction - Meiosis I]
  
==Signs and Symptoms==
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[http://www.biostudio.com/d_%20Meiotic%20Nondisjunction%20Meiosis%20II.htm Animation Meiotic Non-disjunction - Meiosis II]
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<gallery caption="Images of Non-disjunction" widths="240px" heights="190px" align="center" perrow="3">
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File:Meiotic non-disjunction.jpg |Figure 6: Meiotic Non-disjunction in Comparison with Normal Disjunction.
  
Screening is recommended when the following signs of Klinefelter syndrome are observed.
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File:Nondisjunction of Homologous Chromosomes in Meiosis1.jpg |Figure 7: Nondisjunction of Homologous Chromosomes in Meiosis 1.
  
• Infertility
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File:Nondisjunction of Sister Chromatids in Meiosis 2.jpg |Figure 8: Nondisjunction of Homologous Chromosomes in Meiosis 2.
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</gallery>
  
• Delayed speech and language development
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===Anaphase Lagging===
  
• Accelerated growth in height
+
In the anaphase phase of cell division, spindle fibers attach to sister chromatids and separate them. However, in the abnormal event of anaphase lagging, some spindle fibers are missing. Because of this, sister chromatid will not be successfully separated but together will be incorporated into a single daughter nucleus. As a result, the daughter cell will have a supernumerary chromosome.
  
• Subnormal intelligence or mental retardation (severity is proportional to the number of extra X chromosomes)
+
==Pathophysiology==
  
• Behavioral problems or psychological distress
+
Although extensive studies have been made to discover the pathophysiology of Klinefelter’s syndrome(KS), i.e. the link between the supernumerary X and the phenotype, it remains largely unclear. Postulations of the pathophysiology of KS have been derived from comparing the phenotype 47,XXY with other sex chromosome aneuploidies. The correlation with this phenotype is established with higher order sex chromosome aneuploidies , such as 48,XXXY.  However several genetic mechanisms may explain the variability of the phenotype, clinical features, life circumstances, life expectancy and fertility <ref name= "PMID20228051"><pubmed>20228051</pubmed></ref>.  Meiotic failure has essential roles in the parental origin of the X chromosome, gene-dosage effects in conjunction with (possibly skewed) X chromosome inactivation (XCI) and especially spermatogenesis<ref name= "PMID20228051"/>. Typically, when two or more X chromosomes are present in a cell, as in healthy females or sex chromosome disorders like 47,XXY, only one is active. The additional X chromosome is mostly inactive and the X [[#Glossary | '''chromatin''']] is perceived as a Barr body in the periphery of the cell nucleus<ref name=PMID"21521364"><pubmed>21521364</pubmed></ref>.
  
  
+
In addition, both X and Y chromosomes carry short regions of homology termed pseudoautosomal regions (PAR) <ref><pubmed> 20228051</pubmed></ref> which remain active in men and woman <ref name="PMID21521364"/>. They behave as an autosome and function to allow X and Y chromosomes to pair and properly segregate during [[#Glossary | '''meiosis''']] in males. Some genes in the X chromosome which are not homologous to the Y chromosome can escape inactivation and are functionally duplicated in KS males<ref name="PMID21521364"><pubmed>21521364</pubmed></ref>.  PAR1 comprises 2.6Mb of the short arm tips of both X and Y chromosomes, PAR2 at the tips of the long arms spans a much shorter region of 320kb. Since the sequencing of the X chromosome, it has been noted that PAR1 contains at least 24 genes whereas in PAR2 only 4 have been identified and that 10% of X chromosomal genes are specifically expressed in the testis<ref name= "PMID20228051"/>.  
These are the symptoms.
 
  
• Small, firm testes
+
 +
XCI can occur randomly or by imprinting, this is where the paternal X chromosome is silenced in the preimplantation embryo and extraembryonic tissue. Random XCI occurs in the epiblast and can inactivate either the maternally or paternally inherited X chromosome, resulting is an active and inactive chromosome, which is transmitted to descendant cells. Some studies have analysed the random XCI in KS patients, and found that there is a skewed inactivation of one allele and this has been detected in a variety of cases. Many other studies have been conducted and this has led to skewed XCI ranges from around 10-40% of cases in KS patients<ref name= "PMID20228051"/>. 
 +
The X-inactivation centre which initiates XCI contains the X (inactive) specific transcript (XIST). XIST encodes an untranslated RNA which can coat and silence the X chromosome. In addition to non-coding transcripts, XCI involves chromatin modifiers and factors of nuclear organisation. Together these lead to a changed chromatin structure and spatial reorganisation of the silenced X chromosome<ref name= "PMID20228051"/>. However, PARs are not inactivated to achieve the same gene-dosage in both sexes. PARs are important because they allow the correct order and fusion of X and Y chromosomes. Clearly, in the case of KS, this fusion is not correct since XXY results and there is the inclusion of an extra X chromosome in the genotype<ref name="PMID16601196"><pubmed>16601196</pubmed></ref>. Therefore, the pseudoautosomal region has a mutation. This mutation can lead to other various genetic disorders as well as KS and the mutation being present in PAR1 or PAR2 can have a similar effect. These mutations will proceed to give rise to the clinical manifestations of KS <ref name="PMID16601196"/>.
  
• Small penis
+
The cardinal features  of KS will arise from the error in germ cell survival in the aneuploid testis in the embryo. When the child reaches puberty, the germ cells are destroyed instead of proliferating the seminiferous tubules. This causes some of the symptoms of KS, such as azoospermia with the formation of small testis. For more information, see the table on [[#Signs and Symptoms | '''signs and symptoms''']] .
  
• Decreased pubic, facial and armpit hair
+
[[File:Diagram of PAR-1 and PAR-2 in humans.PNG|thumb|800px|center|Figure 9: Diagram of PAR-1 and PAR-2 in humans]]
  
• Enlarged breast
+
==Signs and Symptoms==
  
• Tall physique
+
Symptoms may differ slightly depending on the stage of development.  Screening is recommended when a combination of the following signs of Klinefelter’s syndrome(KS) are observed.
  
• Abnormal body proportions (long limbs and short trunk)
+
{|  width="90%" cellspacing="1" cellpadding="1"
 +
|-bgcolor="DDCEF2"
 +
|  <b>Age</b>
 +
|  <b>Signs and Symptoms</b>
 +
|  <b>Image and Links</b>
 +
|-
 +
|  '''Birth'''
 +
 +
* [[#Glossary | '''Cryptorchidism''']]
 +
*Small penis
 +
*[[#Glossary | '''Hypotonia''']]
 +
*Scrotum Bifidus
 +
*Inguinal Hernia
 +
*Cleft Palate<ref>http://www.genome.gov/19519068</ref>
 +
| [[File: Comparing age and intellect of a Klinefelter group a non-clinical control group.PNG|thumb|center|Figure 10. Comparing age and intellect of a KS group and a non-clinical control group]]
 +
|-bgcolor="FAF5FF"
 +
|  '''Infancy'''
 +
 +
* Learning difficulties (severity is proportional to number of extra X chromosomes)
 +
*Delayed speech and language deficits
 +
*Motor delay or dysfunction
 +
*Attention deficits
 +
*Small penis and testes
 +
*Long limbs<ref>http://emedicine.medscape.com/article/945649-clinical#a0217</ref>
 +
|-
 +
|  '''Childhood'''
 +
 +
* Small, firm testicles
 +
*Verbal cognitive deficits
 +
*Speech difficulties
 +
*Trouble with spelling, reading and mathematics
 +
*Mood and Behavioral problems
 +
*Difficulty expressing feelings and socializing<ref>Schlatt S, Hillier SG &Foresta C, ''' Klinefelter’s syndrome: from chromosome to clinic''' Molecular Human Reproduction 2010;16: 373– 374</ref>
 +
|-bgcolor="FAF5FF"
 +
|  '''Puberty'''
 +
 +
* [[#Glossary | '''Gynecomastia''']] <ref name="PMID19221583"><pubmed>19221583</pubmed></ref>
 +
*Long limbs but short trunk
 +
*Above average, accelerated height
 +
*Reduced muscle bulk
 +
*Scarce facial and body hair
 +
*Delayed or incomplete pubertal development
 +
*Low energy levels
 +
*Require speech and/or educational support<ref>Aksglæde L, Skakkebæk NE, Almstrup K, Juul A. '''Clinical and biological parameters in 166 boys, adolescents and adults with nonmosaic Klinefelter syndrome: a Copenhagen experience.'''Acta Pædiatrica 2011, 100(6);793–806</ref>
 +
| [[File:Pubertal_gynecomastia_1.jpg|thumb|center|Figure 11. Enlargement of the male breast, which is commonly seen in the pubertal period]]
 +
|-
 +
|  '''Adulthood'''
 +
 +
* Mental difficulties  (eg. unable to make plans or solve problems)
 +
*Osteoporosis (due to decreased bone mineral density) <ref>Daniel JW, MAJ, MC, USAF, and Maximilian M, M.D. '''Klinefelter Syndrome''' Am Fam Physician. 2005 Dec 1;72(11):2259-2262.</ref>
 +
*Abnormal reproductive hormone indicated by an unusual LH ⁄ testosterone ratio
 +
*Progressive seminiferous tubules deterioration
 +
*Great hyperplasia of the Leydig cell indicated by extremely low inhibin B levels and above average FSH and LH levels
 +
*Infertility due to a lack of sperm
 +
*Under average testicular volume
 +
*Problem with penile erection
 +
*Decreased [[#Glossary | '''Libido''']]
 +
*High chance of being diagnosed psychiatric disorders, such as Schizophrenia, Bipolar disorder and Delusional disorder<ref name="PMID21655260"><pubmed>21655260</pubmed></ref>
 +
*Less[[#Glossary | '''smooth pursuit eye movements''']]<ref name="PMID21655260"/>
 +
*Lesser ability to adapt to stimulus<ref name="PMID21655260"/> As seen in figure 12-13, the height of the startle decreased as the nervous system has adapted to the [[#Glossary | '''prepulse''']]. However when  comparing the two graphs, after a prepulse, the height of the startle experienced by the KS group decreased by a lesser extent, when compared to the control group. This illustrates that KS patient can not adapt to stimulus as well and thus will experience sensory overload and disjunctional cognition.
 +
| [[File:Control group response to startle.jpg|thumb|center|Figure 12. EMG potentials in the control group of normal male subjects who respond to a startle (black line) and a startle after a prepulse (red line).]]
 +
| [[File:Klinefelter syndrome group response to startle.jpg|thumb|center|Figure 13. EMG potentials in the KS group who respond to a startle (black line) and a startle after a prepulse (red line).]]
 +
|-
 +
|}
  
  
<ref>http://www.genome.gov/19519068</ref>
+
[http://onlinelibrary.wiley.com/doi/10.1111/j.1651-2227.2011.02246.x/pdf Link to an article which has images which compares testicular specimens from various age groups]
<ref>http://emedicine.medscape.com/article/945649-clinical#a0217</ref>
 
  
 
==Diagnosis==
 
==Diagnosis==
  
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.
+
===Karyotype===
 
<ref>http://www.genome.gov/19519068</ref>
 
  
==Aetiology==
+
Karyotyping is a process where the number of chromosomes and their structures are observed for any abnormalities. In a healthy male subject, the [[#Glossary | '''karyotype''']] analysis will show 46,XY. But in a Klinefelter's syndrome(KS) patient, the [[#Glossary | '''karyotype''']] is often observed to be 47,XXY. The featured image is an example of a typical [[#Glossary | '''karyotype''']] of a KS patient.
 +
 
 +
[http://www.youtube.com/watch?v=F7trv8c3Vlo Movie on the process of karyotyping]
 +
 
 +
===Statistics===
  
Chromosome abnormalities have a high incidence in humans. The most common type is aneuploidy, which is the loss (monosomy) or gain (trisomy) of an entire chromosome <ref><pubmed>12926525</pubmed></ref>. Aneuploidy’s occur in approximately 5% of pregnancies which survive long enough to be seen and approximately 10-25% of all fertilised human oocytes are either monosomic or trisomic <ref><pubmed>12926525</pubmed></ref>. Trisomies are incapable of normal development, the consequences are less severe for the sex chromosomes than the autosomes, leading to enhanced sex chromosomes among live-borns in comparison with autosomal trisomies. Therefore, the 47,XXY condition, termed Klinefelter’s Syndrome (KS) is identified in almost 1 of every 1000 male births, causing it to be one of the most commonly identified chromosome abnormality among live-born individuals.  
+
The chances of diagnosing KS are, unfortunately, very low. In one study, only 36% of KS patients are diagnosed, of which 10% of the KS patients being diagnosed prenatally and 26% post natally. This shows that diagnosis methods are not easily accessed and performed.
 +
<ref>Abramsky L, Chapple J. '''47,XXY (Klinefelter syndrome) and 47,XYY: estimated rates of and indication for postnatal diagnosis with implications for prenatal counselling.''' Prenat Diagn 1997;17:363 – 368</ref>
  
 +
===Prenatal Diagnosis methods===
  
'''Non-disjunction'''
+
Prenatal diagnosis is most common achieved by two methods, either by amniocentesis or chorionic villus sampling (CVS). As both are invasive procedures, they have considerable risks. Most often these diagnosis methods are performed because other genetic defects are suspected, such as Down ’s syndrome, because of an advanced maternal age. Therefore, the diagnosis of KS is often considered a chance finding.
  
[[File:Maternal Non-Disjunction.PNG|right|300px|'''Figure 1. Maternal Non-disjunction|thumb''']]
+
Amniocentesis can be done from approximately 14 weeks gestation, it involves the sampling of amniotic fluid. The amniotic fluid contains fetal DNA and cells, proving very useful for such
 +
testing.
 +
[[File:Karyotype of a Klinefelter's syndrome patient.jpg|right|300px|Figure 14. Karyotype of KS|thumb]]A needle is passed into the mother’s abdomen and into the amniotic cavity. This process is always used in conjunction with an ultrasound, to ensure the best conditions are available, ie fetal position in womb. <ref><pubmed>15758614</pubmed></ref>
  
Non-disjunction is the failure of chromosome pairs to separate during the first and second meiotic divisions. Maternal XXY can be caused by non-disjunction during the first and second meiotic divisions, however, XXY of paternal origin can only occur during the first meiotic division. In the great majority of trisomies the additional chromosome is of maternal origin and results from an error during the first meiotic division as seen in figure 1. However, the 47,XXY has been extensively studied and around one half of all cases are paternally derived. The nature of the errors by which maternal and paternal XXYs can arise are extremely diverse. The process of meiosis serves to generate haploid gametes through a specialised cell division process, consisting of two stages of cell division, MI and MII. During prophase of MI the pairs of homologous chromosomes synapse and undergo recombination, with chiasmata being formed at the sites of exchange. Their purpose is to link together the homologues and therefore play a crucial role in the proper disjunction of chromosomes in the first meiotic division.  
+
For CVS, a catheter is passed through the mother’s vagina and into the uterus using ultrasound imaging. From here, cells from the chorionic placenta can be sampled for future testing. This can be carried out in the first trimester of pregnancy, a significant benefit over amniocentesis. However, there is a risk of miscarriage with this test, especially when compared to the process amniocentesis. <ref><pubmed>21413037</pubmed></ref>
  
 +
The cells from both samples are then cultured until there are sufficient numbers of cells. An enzyme is then added that halts proliferation at a point when the chromosomes are condensed. These chromosomes are then stained and, using a light microscope, any abnormalities can be identified. <ref><pubmed>135003</pubmed></ref>
  
 +
===Diagnosis at birth===
  
'''Genetics'''
+
Although this rarely takes place, some clinical features may make physicians suspect and ask for a [[#Glossary | '''karyotype''']] analysis.
 +
Some abnormalities include:
  
Although many other genes are important for proper sexual development of the male foetus, the SRY (sex-determining region of Y chromosome) gene located on the Y chromosome directs the development of the foetal gonads into testes. Typically, when two or more X chromosomes are present in a cell, as in healthy females or sex chromosome disorders like 47,XXY, only one is active. The additional X chromosome is mostly inactive and the X chromatin is perceived as a Barr body in the periphery of the cell nucleus. <ref><pubmed> 21521364</pubmed></ref>
+
•  genital abnormalities (eg. cryptorchidism, small penis, scrotum bifidus and hypospadias)
In addition to specific regions, both sex chromosomes carry short regions of homology termed pseudoautosomal regions (PAR) <ref><pubmed> 20228051</pubmed></ref> which remain active in men and woman <ref><pubmed> 21521364</pubmed></ref>. They behave as an autosome and function to allow X and Y chromosomes to pair and properly segregate during meiosis in males. Some genes in the X chromosome which are not homologous to the Y chromosome can escape inactivation and are functionally duplicated in KS males. <ref><pubmed> 21521364</pubmed></ref>
 
  
==Pathogenesis==
+
•  fifth finger clinodactyly
  
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.
+
•  cleft palate
  
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.
+
•  inguinal hernia <ref>Lee YS, Wai Fun Cheng A, Ahmed SF, Shaw JN, Hughes AI. '''Genital anomalies in Klinefelter’s Syndrome.''' Horm Res 2007;68:150 – 155.</ref>
  
 +
===Postnatal Diagnosis Methods===
  
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.
+
[[File:Fluorescence In situ Hybridization (FISH) assay.JPG|Figure. 15 FISH showing the number of X chromosomes within a nuclei|thumb|right|300px]]
  
<ref>Cynthia M. Smyth, MD; William J. Bremner, MD, PhD Klinefelter Syndrome. Arch Intern Med. 1998;158:1309-1314</ref>
+
Postnatal diagnositic test for KS are often performed because physicians may suspect it because of clinical findings. As described in the ‘Signs and Symptoms’ section, some clinical findings may include patients suffering from infertility, learning disabilities and osteoporosis. Furthermore, a blood test of a KS patient may show high levels of follicle stimulating hormone, luteinizing hormone and low levels of testosterone. <ref>http://tidsskriftet.no/article/1695231 Week. 11 - 29 May 2008 Journal of Medical Unite 2008: 128:1281-3</ref>
  
 +
Postnatal karyotyping is a process where a blood sample is analysed. [[#Glossary | '''Leukocytes''']] from the patient’s blood sample are separated and then cultured. They are halted in the cell cycle when the chromosomes are condensed and can be stained. A photograph is taken of the chromosomes from one cell. Then they are organized according to size, number and structure and then observed for abnormalities.<ref><pubmed>15183749</pubmed></ref><ref>http://www.genome.gov/19519068</ref>
  
 
==Management==
 
==Management==
Line 143: Line 323:
 
===Androgen Therapy===
 
===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<ref><pubmed>20482304</pubmed></ref>.
+
[[#Glossary | '''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<ref><pubmed>20482304</pubmed></ref>.
  
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. <ref><pubmed>21362043</pubmed></ref>
+
Samango-Sprouse ''et al'' found that the initiation of [[#Glossary | '''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 KS - 49,XXXXY.  This gives much hope to the prospect of early treatment resulting in normal development of those afflicted with KS. <ref><pubmed>21362043</pubmed></ref>
  
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<ref><pubmed>18832949</pubmed></ref>. It is also recommended to stop testosterone replacement a few months prior to the administration of infertility treatment<ref><pubmed>18832949</pubmed></ref>.
+
[[File:Action of Amoratase Inhibitors on Production of Estradiol.JPG|right|thumb|Figure 16. Action of Inhibitors on the Conversion of Testosterone to Estradiol]]
  
 +
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<ref name="PMID18832949"/>.  It is also recommended to stop testosterone replacement a few months prior to the administration of infertility treatment<ref name="PMID18832949"><pubmed>18832949</pubmed></ref>. <ref><pubmed>21655260</pubmed></ref>
  
 
===Fertility===
 
===Fertility===
  
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<ref><pubmed>11792932</pubmed></ref>.  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<ref><pubmed>21811543</pubmed></ref>, 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<ref><pubmed>21716935</pubmed></ref>.
+
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 [[#Glossary | '''spermatogenesis''']]<ref name="PMID11792932"><pubmed>11792932</pubmed></ref>.  There are two main methods used to treat non-obstructive [[#Glossary | '''azoospermia''']], microdissection testicular sperm extraction (TESE) and conventional TESE.  These are methods of extracting what sperm is present in the testes for use in [[#Glossary | ''' ''in vitro'' fertilisation''']] (IVF).  
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. <ref><pubmed>11792932</pubmed></ref><ref><pubmed>19616796</pubmed></ref>
+
It has been shown that microdissection TESE has a higher rate of extraction, and allows for minial testicular damage<ref><pubmed>21811543</pubmed></ref>, 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<ref><pubmed>21716935</pubmed></ref>.
 +
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<ref name="PMID11792932"><pubmed>11792932</pubmed></ref>.
  
 
==Other Similar Defects==
 
==Other Similar Defects==
Line 167: Line 349:
 
|  '''Turner Syndrome (XO)'''
 
|  '''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 <ref><pubmed>21454226</pubmed></ref>.
 
|  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 <ref><pubmed>21454226</pubmed></ref>.
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 <ref><pubmed>21271130</pubmed></ref>.
+
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 [[#Glossary | '''dysgenesis''']]. As well as all this, there may also be congenital defects of the heart, kidney and autoimmune system <ref><pubmed>21271130</pubmed></ref>.
 
|   
 
|   
*Abnormal karyotype
+
*Abnormal [[#Glossary | '''karyotype''']]
 
*People are also generally infertile
 
*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
 
*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 <ref><pubmed>21818630</pubmed></ref>
+
*People with Klinefelter’s syndrome(KS) and Turners may both have learning difficulties, and difficulties with social interaction <ref><pubmed>21818630</pubmed></ref>
 
|   
 
|   
 
*Results from the loss of a chromosome, as opposed to the addition of  a chromosome  
 
*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
+
*Many females with Turner’s syndrome have normal intelligence, whereas males with KS tend to have slightly below average intelligence
| [[File:Immunoglobulin levels in 15 girls with Turner Syndrome.png|thumb|center|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)]]
+
| [[File:Immunoglobulin levels in 15 girls with Turner Syndrome.png|thumb|center|Figure 17. 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)]]
 
|-bgcolor="FAF5FF"
 
|-bgcolor="FAF5FF"
 
|  '''47,XYY'''
 
|  '''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 <ref><pubmed>10545600</pubmed></ref>.  This condition only affects males.
+
|  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 [[#Glossary | '''gametogenesis''']] <ref><pubmed>10545600</pubmed></ref>.  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 <ref><pubmed>18037669</pubmed></ref>.
+
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 [[#Glossary | '''karyotype''']] <ref><pubmed>18037669</pubmed></ref>.
 
|  
 
|  
 
*Results from the addition of a chromosome   
 
*Results from the addition of a chromosome   
Line 188: Line 370:
 
*The condition is completely asymptomatic in most cases, this is the reason for the debate regarding whether it should be termed a ‘syndrome’
 
*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 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 <ref><pubmed>20014371</pubmed></ref>
+
*Boys with 47,XYY syndrome tend to have some impairment in language development, albeit minor, whereas boys with KS have some form of motor impairment function <ref><pubmed>20014371</pubmed></ref>
| [[File:Karyogram of male with 47, XYY Syndrome.png|thumb|center|Karyogram of male with 47,XYY Syndrome]]
+
| [[File:Karyogram of male with 47, XYY Syndrome.png|thumb|center|Figure 18. Karyogram of male with 47,XYY Syndrome]]
 
|-  
 
|-  
 
|  '''48,XXYY'''
 
|  '''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 <ref><pubmed>3714610</pubmed></ref>.
+
|  48,XXYY, frequently referred to as another variant of KS, 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 <ref><pubmed>3714610</pubmed></ref>.
 
|   
 
|   
*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 <ref><pubmed>18481271</pubmed></ref>
+
*The physical phenotype of the condition is very similar to KS, since males have a tall stature, have learning disabilities and are infertile <ref><pubmed>18481271</pubmed></ref>
 
|   
 
|   
* 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 <ref><pubmed>8389624</pubmed></ref>
+
* In some cases, signs of [[#Glossary | '''acromegaly''']] have been seen in some patients with this variant, as demonstrated in a study of a 24 year old male living in Japan <ref><pubmed>8389624</pubmed></ref>
| [[File:Male with 48,XXYY Syndrome.png|thumb|center|Male with 48,XXYY Syndrome]]
+
| [[File:Male with 48,XXYY Syndrome.png|thumb|center|Figure 19. Male with 48,XXYY Syndrome]]
 
|-bgcolor="FAF5FF"
 
|-bgcolor="FAF5FF"
 
|}
 
|}
  
 +
==Current Research==
  
==Current Research==
+
'''Neural systems for social cognition in Klinefelter syndrome(KS) (47,XXY): evidence from fMRI; 2011'''
  
'''Neural systems for social cognition in Klinefelter syndrome (47,XXY): evidence from fMRI; 2011'''
+
[[File:FMRI Images of Brain Activation in XXY Patients.JPG|Figure 20. fMRI Images of Brain Activation in XXY Patients|thumb|300px]]
  
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 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 KS 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 KS 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. <ref><pubmed>21737434</pubmed></ref>
+
It was found that KS can be associated with decreased activity in specific neural systems.  This also advocates the possibility of using KS as a model for further study of the X chromosome. <ref><pubmed>21737434</pubmed></ref>
  
  
 
'''Insights into the pathogenesis of XXY phenotype from comparison of the clinical syndrome with an experimental XXY mouse model; 2010'''
 
'''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.   
+
Even after all we now know about KS, 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 KS are likely due to an avoidance of the inactivation of the X chromosome. <ref><pubmed>21217605</pubmed></ref>
  
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. <ref><pubmed>21217605</pubmed></ref>
 
  
 +
'''Expression of selected genes escaping from X inactivation in the 41, XXY* mouse model for Klinefelter’s syndrome(KS); 2010'''
  
'''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 KS.  It has been suggested that some of the genes on the X chromosome escape inactivation and so result in the clinical symptoms of KS.  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. 
  
It still remains a debate as to the exact molecular and genetic actions that result in the presentation of Klinefelter's syndromeIt 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 to that of 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. <ref><pubmed>21241365</pubmed></ref>
  
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. <ref><pubmed>21241365</pubmed></ref>
+
==Related Links==
  
 +
'''Internal'''
 +
 +
*[http://embryology.med.unsw.edu.au/embryology/index.php?title=Oocyte_Development Oocyte Development] | This page describes the normal development of an oocyte, also discussing the abnormalities associated such as non-disjunction.
 +
 +
*[http://embryology.med.unsw.edu.au/embryology/index.php?title=2010_BGD_Practical_3_-_Gametogenesis Gametogenesis] | This page, similarly, describes the normal development of the gametes and the associated abnormalities.  The relate to the development of Klinefelter's syndrome.
 +
 +
*[http://embryology.med.unsw.edu.au/embryology/index.php?title=Cell_Division_-_Meiosis Cell Division - Meiosis] | This page describes the process of meiosis and the possible associated irregularities such as non-disjunction.
 +
 +
*[http://embryology.med.unsw.edu.au/embryology/index.php?title=Abnormal_Development_-_Genetic Abnormal Development - Genetic] | This page largely discusses the possible genetic abnormalities and their formation such as aneuploidy, which is the cause of Klinefelter's syndrome.
 +
 +
*[http://embryology.med.unsw.edu.au/embryology/index.php?title=Lecture_-_Genital_Development Genital Development] | Irregular genital development is one of the major symptoms associated with Klinefelter's syndrome.  This page gives an overview of normal genital development and the associated abnormalities.
 +
 +
 +
'''External'''
 +
 +
*[http://www.andrologyaustralia.org/pageContent.asp?pageCode=KLINEFELTERSSYNDROME Andrology Australia] | This page gives a concise summary of Klinefelter's syndrome.
 +
 +
*[http://www.apeg.org.au/Portals/0/resources/hormones%20&%20me%20klinefelter%20syndrome%20may%202011.pdf Information booklet] | This is a detailed information booklet regarding Klinefelter's syndrome, published by the Australian Paediatric Endocrine Group
  
 
==Glossary==
 
==Glossary==
  
===A===
+
*'''Acromegaly'''  -  This is a condition caused by abnormal hormone production from the pituitary gland, resulting in altered growth of hands, feet, and face
'''Acromegaly'''  -  This is a condition caused by abnormal hormone production from the pituitary gland, resulting in altered growth of hands, feet, and face
+
 
 +
*'''Anaphase lag'''  -  Describes a chromosome which is not incorporated into the new cell in the second stage of mitosis(anaphase) due to it ‘lagging’, resulting in gametes lacking a sex chromosome
 +
 
 +
*'''Androgen'''  -  A male sex hormone, ie testosterone
 +
 
 +
*'''Aneuploidy'''  -  Abnormal number of chromosomes
 +
 
 +
*'''Azoospermia'''  -  Occurs when males have little to no motile sperm in the semen
  
'''Androgen'''  -  A male sex hormone, ie testosterone
+
*'''Barr bodies'''  -  Inactivated X chromosome in females due to sex being determined by W or Y chromosomes instead of XY
  
'''Aneuploidy'''  -  Abnormal number of chromosomes
+
*'''Buccal mucosal cells'''  -  Cells of the oral cavity that secrete mucus
  
'''Azoospermia'''  -  Occurs when males have little to no motile sperm in the semen
+
*'''Chromatin'''  -  The genetic material that forms chromosomes, it is also composed of DNA
  
===B===
+
*'''Cryptorchidism''' - 1 or 2 testes have not dropped into the scrotum from the abdominal cavity
'''Barr bodies''' - Inactivated X chromosome in females due to sex being determined by W or Y chromosomes instead of XY
 
  
'''Buccal mucosal cells'''  -  Cells of the oral cavity that secrete mucus
+
*'''Dysgenesis'''  -  Defective or abnormal development of an organ, especially of the gonads
  
===C===
+
*'''Gametogenesis'''  -  Biological process by which haploid or diploid cells undergo division and/or differentiation to form mature haploid gametes.
'''Chromatin'''  -  The genetic material that forms chromosomes, it is also composed of DNA
 
  
===D===
+
*'''Gonadotropin'''  -  Protein hormones secreted by gonadotrope cells of the pituitary gland.
'''Dysgenesis'''  -  Defective or abnormal development of an organ, especially of the gonads
 
  
===G===
+
*'''Gynecomastia'''  -  Is the abnormal development of large mammary glands in males which give large breasts.  
'''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.
+
*'''Hyalinised'''  -  The state of something being hyaline (clear and translucent)
  
'''Gynecomastia'''  -  Is the abnormal development of large mammary glands in males which give large breasts.  
+
*'''Hypogonadism'''  -  Occurs when the sex glands produce little to no hormones.
  
===H===
+
*'''Hypotonia''' - reduced muscle tone
'''Hyalinised''' - The state of something being hyaline (clear and translucent)
 
  
'''Hypogonadism'''  -  Occurs when the sex glands produce little to no hormones.
+
*'''In vitro fertilisation'''  -  The process of fertilising an oocyte by sperm outside the womb.
  
===I===
+
*'''Karyotype'''  -  Number and/or appearances of chromosomes in a eukaryotic cell nucleus
'''In vitro fertilisation'''  -  The process of fertilising an oocyte by sperm outside the womb.
 
  
===K===
+
*'''Leukocytes'''  -  White blood cells which are cells of the immune system
'''Karyotype'''  -  Number and/or appearances of chromosomes in a eukaryotic cell nucleus
 
  
===L===
+
*'''Libido''' - sexual desire
'''Leukocytes''' - White blood cells which are cells of the immune system
 
  
===M===
+
*'''Meiosis'''  -  The process of cell division of germ (sex) cells resulting in 4 daughter cells.
'''Meiosis'''  -  The process of cell division of germ (sex) cells resulting in 4 daughter cells.
 
  
'''Mosaicism'''  -  The presence of two or more genetically different cells in one organism
+
*'''Mosaicism'''  -  The presence of two or more genetically different cells in one organism
  
===N===
+
*'''Non-disjunction'''  -  The failure of chromosomes to separate properly during cell division.  This results in abnormal chromosome number in daughter cells.
'''Non-disjunction'''  -  The failure of chromosomes to separate properly during cell division.  This results in abnormal chromosome number in daughter cells.
 
  
===P===
+
*'''Pituitary gland'''  -  Endocrine gland that secretes hormones that regulate homeostasis.
'''Pituitary gland'''  -  Endocrine gland that secretes hormones that regulate homeostasis.
 
  
'''Post zygotic non-disjunction'''  -  This occurs when chromosomes do not separate during mitosis, and the cells are not removed by the usual 'proof-reading' mechanisms.
+
*'''Post zygotic non-disjunction'''  -  This occurs when chromosomes do not separate during mitosis, and the cells are not removed by the usual 'proof-reading' mechanisms.
  
===S===
+
*'''Prepulse''' - A weak stimulus that inhibits a reaction to the following stimulus.
'''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
+
*'''Seminiferous tubule'''  -  Long, thread like tubes found in the testes and are the specific location of meiosis in the body.
  
'''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.
+
*'''Sertoli cells'''  -  Cell of the testes that is part of the seminiferous tubule. It is activated by Follicle Stimulating Hormone
 +
 
 +
*'''Smooth pursuit eye movements''' - A slow and trailing eye movement which allows the moving object of attention to remain in line with the fovea.[http://www.ncbi.nlm.nih.gov/books/NBK10981/ Definition from the Neuroscience textbook]
 +
 
 +
*'''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===
 
'''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.
 
  
  
 
==References==
 
==References==
 +
 +
 
<references/>
 
<references/>
 
----
 
----
  
 
{{2011Projects}}
 
{{2011Projects}}

Latest revision as of 10:32, 4 April 2012

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


Introduction

Figure 1: 47,XXY Klinefelter's Syndrome

Klinefelter's syndrome, first described in 1942 by Harry F. Klinefelter[1], is caused by the addition of one or more X chromosome(s) in affected males . He depicted a disorder characterised by gynecomastia and a very specific type of hypogonadism, as well as an absence of spermatogenesis.

It is still largely associated with these defects, the most common including reduced fertility and hypogonadism. A high proportion of affected men may remain asymptomatic their whole lives, this is because the severity of the disorder differs greatly from person to person[2].

The extra chromosome present is largely due to a genetic abnormality known as non-disjunction that can occur during either mitosis or meiosis, this is described in more detail below and portrayed in Figure 1. It has also been suggested to be the most common disorder associated with non-disjunction [2]

There are a number of diagnostic techniques currently used to determine accurate and early identification of the syndrome. This is particularly useful to encourage the implementation of the best treatment plan to manage the symptoms of the syndrome[3]. The phenotype of the syndrome differs significantly through the different stages of life, and a particular stage will correspond to the best management protocol for that point.





History

Figure 2: Steps in a classic array CGH-analysis used for the most common chromosomal abnormalities

Klinefelter syndrome (KS) 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, azoospermia, hyalinised and small testes, absent spermatogenesis, elevated levels of follicle-stimulating hormone (FSH) and hypogonadism[4] [2]

In 1956, an investigation was carried out with 7 patients with KS that had the buccal smears that demonstrated Barr bodies . However, the cause of the syndrome remained unknown until 1959, when Jacobs and Strong discovered that a patient with KS had 47 chromosomes, including an extra X chromosome in the karotype of the patient [4]. As recorded in their article 'A case of human intersexuality having a possible XXY sex-determining mechanism';


“…There are strong grounds, both observational and genetic, for believing that human beings with chromatin-positive nuclei are genetic females having two X chromosomes. The fact that this patient is chromatin-positive and has an additional chromosome within the same size range as the X, as well as an apparently normal Y, makes it seem likely that he has the genetic constitution XXY”[5]


This discovery confirmed that the Barr bodies seen in patients with KS corresponds to an extra X chromosome[5]. In 1966, Harry F. Klinefelter reported that the extra X chromosome results from either meiotic nondisjunction or anaphase lag[6]. The ‘prototypic’ man with KS was initially described as tall, with narrow shoulders, broad hips, sparse body hair, gynecomastia, small testes, androgen deficiency and reduced verbal intelligence[4]. However, a few years after the syndrome was described Heller and Nelson reported that the gynacomastia was not a necessary part of the syndrome, even though it occurred in about 75% of the patients which they observed. The hallmarks of the syndrome were then thought small testes, sterility and increased excretion of follicle stimulating hormone[6]. Extensive studies of these patients during their adolescence illustrated the various personality traits, which can be handled by proper counselling. Similar to today, Harry Klinefelter reported that most patients with this condition were not diagnosed until early adult life, when counselling may be less rewarding.

Below is a timeline highlighting all the major advancements and developments in KS.



Timeline

Year Discovery
1942 Dr. Harry Klinefelter and his co-workers at Massachusetts General Hospital in Boston published a report on 9 men describing the signs and symptoms of KS. The ‘prototypic’ man with KS was described as tall, with narrow shoulders, broad hips, sparse body hair, gynecomastia, small testes, androgen deficiency and reduced intelligence. [4]
1949 Barr and Bertram noticed positive chromatin material in KS patients.It was a dense chromatin mass which they later termed, Barr body.
1956 The discovery of Barr bodies as a result of the new development of Buccal smears
1959 Jacobs and Strong discovered that it was a chromosomal disorder, with the appearance of an extra X chromosome.
1960s Development of chromosome banding techniques. [7]
1962 Maclean and Mitchell’s studies on inmates in prisons and institutions for mental health revealed an increased risk of psychiatric disorders, mental retardations and criminal behaviour in patients with KS. [4]
1966 Dr. Harry Klinefelter reports that the extra X chromosome results from either meiotic non-disjunction or anaphase lag. [6]
1970 Rozen et al reported that approximately 1% of all individuals institutionalised with mental retardation have an XXY karotype. [8]
1970s A number of centres began screening newborns for sex chromatin abnormalities.
1986 Dr. Harry Klinefelter described that the hallmarks of the syndrome are now small testes, sterility and increased excretion of follicle stimulating hormone. [6]

He also reported that most patients with this condition were not diagnosed until early adult life, when counselling may be less rewarding. [6]

Treated hypogonadism with injected testosterone, and thought this also aided personality abnormalities in adolescent patients. [6]

1992 The Comparative Genomic Hybridization (CGH) analysis was developed as a genome wide screening strategy for detecting DNA copy number imbalances.[9] A classic array-CGH experiment is shown in Figure 2.
1995 Reiss et al., found that half all mental retardation in males originates from a defective gene on the X chromosome. Thus, the X chromosome comprises the genes involved in human cognition. [10]
1998 Smyth and Bremmer concluded that XXY karotypes occurs in 1 in 500 live male births and is the most common type of human chromosome anomaly. [11]

They also hypothesised that the characteristics features of KS originate from genes escape inactivation and are expressed in excess.

2002 Crow et al., suggested that at least one gene or genes in the X-Y homologous regions of the sex chromosomes which escape’s normal X- inactivation are crucial for language functioning.[12]
2010 Stefano Gambardella et al., designed a targeted array called GOLD (gain or loss detection) Chip which detects unexpected major chromosome imbalances. [13]

Epidemiology

One of the most common disorders of sex chromosomes in humans is Klinefelter’s syndrome (KS), 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 KS often go through life without being karyotyped, meaning that they are left undiagnosed[15]. In around 80% of cases, the karyotype for KS 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.


A link was found between increased risk of mortality and KS. There was “a significant increase in mortality risk of 40% (hazard ratio, 1.40; 95% confidence interval, 1.13–1.74), corresponding to a significantly reduced median survival of 2.1 yrs.’’ [16]The increased mortality was because of infections, neurological, circulatory, pulmonary, and urinary tract diseases which people with KS are more susceptible too. There are studies currently being conducted into whether socioeconomic background increases the risk of a child developing KS[16].


Seizures can typically occur, and when seizures occur in males with KS, it usually happens between 3 months and 3 years of age. Neuro-imaging tests have failed to identify the cause of the seizures[17]. It is very difficult to diagnose a child with KS immediately, since many of the symptoms that are exhibited in childhood may be due to other factors, such as shyness, stress, and social phobia. Figure 3 is a graph adapted from recent studies, demonstrating the emotional response to stimuli of men with KS compared to normal males. It has also been suggested that men with KS are 50% more at risk of being diagnosed with breast cancer, as shown in Figure 4.[18]

Aetiology

Chromosome abnormalities have a high incidence in humans. The most common type is aneuploidy, which is the loss (monosomy) or gain (trisomy) of an entire chromosome [19]. Aneuploidy’s occur in approximately 5% of pregnancies which survive long enough to be seen and approximately 10-25% of all fertilised human oocytes are either monosomic or trisomic [19]. Trisomies are incapable of normal development, the consequences are less severe for the sex chromosomes than the autosomes, leading to enhanced sex chromosomes among live-borns in comparison with autosomal trisomies. Abnormal chromosome distribution, is the result of one of two mechanisms; non-disjunction and anaphase lagging. However, Klinefelter’s syndrome(KS) is more commonly caused by non-disjunction.[20]


Non-Disjunction

Figure 5:Maternal Non-disjunction.


Non-disjunction is the failure of chromosome pairs to separate during the first and second meiotic divisions, as shown in Figure 5. Maternal XXY can be caused by non-disjunction during the first and second meiotic divisions, however, XXY of paternal origin can only occur during the first meiotic division. In the great majority of trisomies the additional chromosome is of maternal origin and results from an error during the first meiotic division as seen in Figure 5. However, the 47,XXY has been extensively studied and there is a 50-60% chance of it being from a paternal origin and 40-50% from a maternal origin[21]. The nature of the errors by which maternal and paternal XXYs can arise are extremely diverse. Studies have established that increased maternal age has adverse affects on pregnancy and an increased chance of anueploidy.[22] The process of meiosis serves to generate haploid gametes through a specialised cell division process, consisting of two stages of cell division, MI and MII. During prophase of MI the pairs of homologous chromosomes synapse and undergo recombination, with chiasmata being formed at the sites of exchange. Their purpose is to link together the homologues and therefore play a crucial role in the proper disjunction of chromosomes in the first meiotic division [19].


This more common aberrant cell division takes place during gametogenesis. More specifically, it is the event of the homologous chromosome or sister chromatid failing to separate normally.[4] So like anaphase lagging, the distribution of genetic content in the daughter cells is uneven. In addition, it can also occur in both of the meiotic divisions, leading to variants of KS with a greater number of X chromosomes. Some examples of these variants are 48,XXXY and 48,XXXXY. Furthermore, non-disjunction can also take place in postzygotic division. [23]


As depicted in Figure 7, when non-disjunction takes place in the first meiotic division, a homologous pair of chromosomes is not separated in the anaphase 1. The result is one daughter cell having three chromosomes while the other has only one by the end of meiosis -1. The daughter cell with one chromosome is not viable. When the daughter cell with three chromosomes is followed through meiosis two, its own progeny can be seen to include either a parental and maternal X chromosome or two copies of the maternal X chromosome.


However, if non-disjunction occurs in the second meiotic division, then the abnormal separation of genetic material takes place in anaphase 2. This is seen in Figure 8. By the end of the second meiosis one daughter cell contains both sister chromatids of the maternal X chromosome, while the other daughter cell does not contain that maternal genetic material.

The consequence of non-disjunction is that an XX ovum or a XY sperm will be produced. This gamete will then go on to be fertilised by a normal Y sperm or an X ovum respectively and conclusively produce a XXY zygote, which is the hallmark of KS.


Animation Meiotic Non-disjunction - Meiosis I

Animation Meiotic Non-disjunction - Meiosis II

Anaphase Lagging

In the anaphase phase of cell division, spindle fibers attach to sister chromatids and separate them. However, in the abnormal event of anaphase lagging, some spindle fibers are missing. Because of this, sister chromatid will not be successfully separated but together will be incorporated into a single daughter nucleus. As a result, the daughter cell will have a supernumerary chromosome.

Pathophysiology

Although extensive studies have been made to discover the pathophysiology of Klinefelter’s syndrome(KS), i.e. the link between the supernumerary X and the phenotype, it remains largely unclear. Postulations of the pathophysiology of KS have been derived from comparing the phenotype 47,XXY with other sex chromosome aneuploidies. The correlation with this phenotype is established with higher order sex chromosome aneuploidies , such as 48,XXXY. However several genetic mechanisms may explain the variability of the phenotype, clinical features, life circumstances, life expectancy and fertility [24]. Meiotic failure has essential roles in the parental origin of the X chromosome, gene-dosage effects in conjunction with (possibly skewed) X chromosome inactivation (XCI) and especially spermatogenesis[24]. Typically, when two or more X chromosomes are present in a cell, as in healthy females or sex chromosome disorders like 47,XXY, only one is active. The additional X chromosome is mostly inactive and the X chromatin is perceived as a Barr body in the periphery of the cell nucleus[25].


In addition, both X and Y chromosomes carry short regions of homology termed pseudoautosomal regions (PAR) [26] which remain active in men and woman [27]. They behave as an autosome and function to allow X and Y chromosomes to pair and properly segregate during meiosis in males. Some genes in the X chromosome which are not homologous to the Y chromosome can escape inactivation and are functionally duplicated in KS males[27]. PAR1 comprises 2.6Mb of the short arm tips of both X and Y chromosomes, PAR2 at the tips of the long arms spans a much shorter region of 320kb. Since the sequencing of the X chromosome, it has been noted that PAR1 contains at least 24 genes whereas in PAR2 only 4 have been identified and that 10% of X chromosomal genes are specifically expressed in the testis[24].


XCI can occur randomly or by imprinting, this is where the paternal X chromosome is silenced in the preimplantation embryo and extraembryonic tissue. Random XCI occurs in the epiblast and can inactivate either the maternally or paternally inherited X chromosome, resulting is an active and inactive chromosome, which is transmitted to descendant cells. Some studies have analysed the random XCI in KS patients, and found that there is a skewed inactivation of one allele and this has been detected in a variety of cases. Many other studies have been conducted and this has led to skewed XCI ranges from around 10-40% of cases in KS patients[24]. The X-inactivation centre which initiates XCI contains the X (inactive) specific transcript (XIST). XIST encodes an untranslated RNA which can coat and silence the X chromosome. In addition to non-coding transcripts, XCI involves chromatin modifiers and factors of nuclear organisation. Together these lead to a changed chromatin structure and spatial reorganisation of the silenced X chromosome[24]. However, PARs are not inactivated to achieve the same gene-dosage in both sexes. PARs are important because they allow the correct order and fusion of X and Y chromosomes. Clearly, in the case of KS, this fusion is not correct since XXY results and there is the inclusion of an extra X chromosome in the genotype[28]. Therefore, the pseudoautosomal region has a mutation. This mutation can lead to other various genetic disorders as well as KS and the mutation being present in PAR1 or PAR2 can have a similar effect. These mutations will proceed to give rise to the clinical manifestations of KS [28].

The cardinal features of KS will arise from the error in germ cell survival in the aneuploid testis in the embryo. When the child reaches puberty, the germ cells are destroyed instead of proliferating the seminiferous tubules. This causes some of the symptoms of KS, such as azoospermia with the formation of small testis. For more information, see the table on signs and symptoms .

Figure 9: Diagram of PAR-1 and PAR-2 in humans

Signs and Symptoms

Symptoms may differ slightly depending on the stage of development. Screening is recommended when a combination of the following signs of Klinefelter’s syndrome(KS) are observed.

Age Signs and Symptoms Image and Links
Birth
Figure 10. Comparing age and intellect of a KS group and a non-clinical control group
Infancy
  • Learning difficulties (severity is proportional to number of extra X chromosomes)
  • Delayed speech and language deficits
  • Motor delay or dysfunction
  • Attention deficits
  • Small penis and testes
  • Long limbs[30]
Childhood
  • Small, firm testicles
  • Verbal cognitive deficits
  • Speech difficulties
  • Trouble with spelling, reading and mathematics
  • Mood and Behavioral problems
  • Difficulty expressing feelings and socializing[31]
Puberty
  • Gynecomastia [32]
  • Long limbs but short trunk
  • Above average, accelerated height
  • Reduced muscle bulk
  • Scarce facial and body hair
  • Delayed or incomplete pubertal development
  • Low energy levels
  • Require speech and/or educational support[33]
Figure 11. Enlargement of the male breast, which is commonly seen in the pubertal period
Adulthood
  • Mental difficulties (eg. unable to make plans or solve problems)
  • Osteoporosis (due to decreased bone mineral density) [34]
  • Abnormal reproductive hormone indicated by an unusual LH ⁄ testosterone ratio
  • Progressive seminiferous tubules deterioration
  • Great hyperplasia of the Leydig cell indicated by extremely low inhibin B levels and above average FSH and LH levels
  • Infertility due to a lack of sperm
  • Under average testicular volume
  • Problem with penile erection
  • Decreased Libido
  • High chance of being diagnosed psychiatric disorders, such as Schizophrenia, Bipolar disorder and Delusional disorder[35]
  • Less smooth pursuit eye movements[35]
  • Lesser ability to adapt to stimulus[35] As seen in figure 12-13, the height of the startle decreased as the nervous system has adapted to the prepulse. However when comparing the two graphs, after a prepulse, the height of the startle experienced by the KS group decreased by a lesser extent, when compared to the control group. This illustrates that KS patient can not adapt to stimulus as well and thus will experience sensory overload and disjunctional cognition.
Figure 12. EMG potentials in the control group of normal male subjects who respond to a startle (black line) and a startle after a prepulse (red line).
Figure 13. EMG potentials in the KS group who respond to a startle (black line) and a startle after a prepulse (red line).


Link to an article which has images which compares testicular specimens from various age groups

Diagnosis

Karyotype

Karyotyping is a process where the number of chromosomes and their structures are observed for any abnormalities. In a healthy male subject, the karyotype analysis will show 46,XY. But in a Klinefelter's syndrome(KS) patient, the karyotype is often observed to be 47,XXY. The featured image is an example of a typical karyotype of a KS patient.

Movie on the process of karyotyping

Statistics

The chances of diagnosing KS are, unfortunately, very low. In one study, only 36% of KS patients are diagnosed, of which 10% of the KS patients being diagnosed prenatally and 26% post natally. This shows that diagnosis methods are not easily accessed and performed. [36]

Prenatal Diagnosis methods

Prenatal diagnosis is most common achieved by two methods, either by amniocentesis or chorionic villus sampling (CVS). As both are invasive procedures, they have considerable risks. Most often these diagnosis methods are performed because other genetic defects are suspected, such as Down ’s syndrome, because of an advanced maternal age. Therefore, the diagnosis of KS is often considered a chance finding.

Amniocentesis can be done from approximately 14 weeks gestation, it involves the sampling of amniotic fluid. The amniotic fluid contains fetal DNA and cells, proving very useful for such testing.

Figure 14. Karyotype of KS

A needle is passed into the mother’s abdomen and into the amniotic cavity. This process is always used in conjunction with an ultrasound, to ensure the best conditions are available, ie fetal position in womb. [37]

For CVS, a catheter is passed through the mother’s vagina and into the uterus using ultrasound imaging. From here, cells from the chorionic placenta can be sampled for future testing. This can be carried out in the first trimester of pregnancy, a significant benefit over amniocentesis. However, there is a risk of miscarriage with this test, especially when compared to the process amniocentesis. [38]

The cells from both samples are then cultured until there are sufficient numbers of cells. An enzyme is then added that halts proliferation at a point when the chromosomes are condensed. These chromosomes are then stained and, using a light microscope, any abnormalities can be identified. [39]

Diagnosis at birth

Although this rarely takes place, some clinical features may make physicians suspect and ask for a karyotype analysis. Some abnormalities include:

• genital abnormalities (eg. cryptorchidism, small penis, scrotum bifidus and hypospadias)

• fifth finger clinodactyly

• cleft palate

• inguinal hernia [40]

Postnatal Diagnosis Methods

Figure. 15 FISH showing the number of X chromosomes within a nuclei

Postnatal diagnositic test for KS are often performed because physicians may suspect it because of clinical findings. As described in the ‘Signs and Symptoms’ section, some clinical findings may include patients suffering from infertility, learning disabilities and osteoporosis. Furthermore, a blood test of a KS patient may show high levels of follicle stimulating hormone, luteinizing hormone and low levels of testosterone. [41]

Postnatal karyotyping is a process where a blood sample is analysed. Leukocytes from the patient’s blood sample are separated and then cultured. They are halted in the cell cycle when the chromosomes are condensed and can be stained. A photograph is taken of the chromosomes from one cell. Then they are organized according to size, number and structure and then observed for abnormalities.[42][43]

Management

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[44].

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 KS - 49,XXXXY. This gives much hope to the prospect of early treatment resulting in normal development of those afflicted with KS. [45]

Figure 16. Action of Inhibitors on the Conversion of Testosterone to Estradiol

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[46]. It is also recommended to stop testosterone replacement a few months prior to the administration of infertility treatment[46]. [47]

Fertility

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[48]. 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[49], 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[50]. 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[48].

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 [51].

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 [52].

  • 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 syndrome(KS) and Turners may both have learning difficulties, and difficulties with social interaction [53]
  • 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 KS tend to have slightly below average intelligence
Figure 17. 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 [54]. 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 [55].

  • 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 KS have some form of motor impairment function [56]
Figure 18. Karyogram of male with 47,XYY Syndrome
48,XXYY 48,XXYY, frequently referred to as another variant of KS, 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 [57].
  • The physical phenotype of the condition is very similar to KS, since males have a tall stature, have learning disabilities and are infertile [58]
  • 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 [59]
Figure 19. Male with 48,XXYY Syndrome

Current Research

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

Figure 20. fMRI Images of Brain Activation in XXY Patients

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 KS 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 KS are generally socially disadvantaged, and so a link was investigated between neural activity and social cues.

It was found that KS can be associated with decreased activity in specific neural systems. This also advocates the possibility of using KS as a model for further study of the X chromosome. [60]


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 KS, 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 KS are likely due to an avoidance of the inactivation of the X chromosome. [61]


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

It still remains a debate as to the exact molecular and genetic actions that result in the presentation of KS. It has been suggested that some of the genes on the X chromosome escape inactivation and so result in the clinical symptoms of KS. 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 to that of 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. [62]

Related Links

Internal

  • Oocyte Development | This page describes the normal development of an oocyte, also discussing the abnormalities associated such as non-disjunction.
  • Gametogenesis | This page, similarly, describes the normal development of the gametes and the associated abnormalities. The relate to the development of Klinefelter's syndrome.
  • Cell Division - Meiosis | This page describes the process of meiosis and the possible associated irregularities such as non-disjunction.
  • Abnormal Development - Genetic | This page largely discusses the possible genetic abnormalities and their formation such as aneuploidy, which is the cause of Klinefelter's syndrome.
  • Genital Development | Irregular genital development is one of the major symptoms associated with Klinefelter's syndrome. This page gives an overview of normal genital development and the associated abnormalities.


External

  • Information booklet | This is a detailed information booklet regarding Klinefelter's syndrome, published by the Australian Paediatric Endocrine Group

Glossary

  • Acromegaly - This is a condition caused by abnormal hormone production from the pituitary gland, resulting in altered growth of hands, feet, and face
  • Anaphase lag - Describes a chromosome which is not incorporated into the new cell in the second stage of mitosis(anaphase) due to it ‘lagging’, resulting in gametes lacking a sex chromosome
  • Androgen - A male sex hormone, ie testosterone
  • Aneuploidy - Abnormal number of chromosomes
  • Azoospermia - Occurs when males have little to no motile 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 of the oral cavity that secrete mucus
  • Chromatin - The genetic material that forms chromosomes, it is also composed of DNA
  • Cryptorchidism - 1 or 2 testes have not dropped into the scrotum from the abdominal cavity
  • 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.
  • Hypotonia - reduced muscle tone
  • In vitro fertilisation - The process of fertilising an oocyte by sperm outside the womb.
  • Karyotype - Number and/or appearances of chromosomes in a eukaryotic cell nucleus
  • Leukocytes - White blood cells which are cells of the immune system
  • Libido - sexual desire
  • Meiosis - The process of cell division of germ (sex) cells resulting in 4 daughter cells.
  • Mosaicism - The presence of two or more genetically different cells in one organism
  • Non-disjunction - The failure of chromosomes to separate properly during cell division. This results in abnormal chromosome number in daughter cells.
  • Pituitary gland - Endocrine gland that secretes hormones that regulate homeostasis.
  • Post zygotic non-disjunction - This occurs when chromosomes do not separate during mitosis, and the cells are not removed by the usual 'proof-reading' mechanisms.
  • Prepulse - A weak stimulus that inhibits a reaction to the following stimulus.
  • 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.


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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