Klinefelter+Syndrome

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Klinefelter syndrome is condition in males that results from an extra X sex chromosome ( 47, XXY; Anagnostopoulas, et al., 2009). The effected male cells have three sex chromosomes, two X and one Y, instead of the normal two sex chromosomes, XY. Depending on the timing of the error leading to Klinefelter Syndrome determines which cells are affected. If there is a random error during meiosis the formation of either the sperm or the egg, every cell in the body will have an extra X chromosome. This error, called nondisjunction, occurs around half the time in egg formation and the other half in sperm formation. If the error occurs early in fetal development, a 46,XY/47,XXY mosaic will occur. This means that only a portion of the body’s cells will contain the extra chromosome.===== Klinefelter Syndrome is one of the most common genetic diseases that effect the male population. The ratio of males born with Klinefelter Syndrome is between 1:500 and 1:1000. The phenotypic differences are usually seen at the onset of puberty. The symptoms of this syndrome have minor long term consequences, and there are various treatments available to supplement testosterone in the body.

 Figure 1. The karyotype of an individual with Klinefelter syndrome (University of Utah, 2012).

__**Symptoms**__
The symptoms that affect males with Klinefelter Syndrome can be seen in various degrees. Some males do not display any symptoms, while others have many feminine characteristics. The number of effected cells in the body, the amount of testosterone in the body, and the age in which Klinefelter Syndrome is diagnosed all contribute to the degree of symptoms. There are three areas of development that Klinefelter affects: physical, language, and social. During early childhood, males with Klinefelter Syndrome have weaker muscles and reduced strength compared to normal males. When entering puberty, XXY males do not produce normal amounts of testosterone, which can lead to larger breasts, weaker bones, and a lower level of energy as teens. Overall, the individual will be taller, have a less muscular body, less facial and body hair, and broader hips. When adulthood is reached, the XXY male will look similar to normal males. The main exception is height difference. Affected males are also more likely to develop secondary health problems such as autoimmune disorders, breast cancer, vein diseases, osteoporosis, and tooth decay. These males do live normal sex lives, except they produce little or no sperm and 95 to 99 percent are infertile because of the low amounts of sperm produced. A large percentage of males develop a form of language problems that include learning to speak late, struggling with the use and expression of thoughts and needs, straining to read and process the sounds they hear. When they reach adulthood, difficulty reading and writing can be more difficult, but they compensate by being more conceptual people by maintaining jobs and having successful careers. When XXY males are babies, they are more likely to be noiseless and unchallenging. As the male ages, they tend to become quieter and less active, lose self-confidence, and turn into more helpful and compliant individuals than other boys of their age. When they become teens, they remain timid and shy. “Fitting in” is difficult for them because they tend to struggle in school and sports. When adulthood is reached, they tend to open up and gain more social relationships with their peers and ultimately live comparable to men without the condition.
 * Physical**
 * Language**
 * Social**

__**Causes of Klinefelter Syndrome**__
The XXY genotype of males with Klinefelter syndrome can arise from several different errors. The main error in development that leads to Klinefelter syndrome is a nondisjunction. Nondisjunction is when the chromosomes do not separate correctly during cell division. In the case of Klinefelter syndrome, the sex chromosomes fail to separate, resulting in an extra X chromosome that is associated with this disease. There are several reasons why the chromosomes would fail to separate during meiosis or mitosis. If the centromere sequence is deleted from a chromsome, the kinetochore proteins will not be able to attach. The lack of kinetochore proteins will not allow the microtubules to attach to the chromosomes, which can result in the chromosome being randomly distributed in the resulting cells. There are spindle apparatus checkpoints during the cell cycle. If the chromosomes do not align properly along the metaphase plate, the cell will perform apoptosis. If this checkpoint is not present, the cell will continue through division with the incorrect chromosome alignment. This can result in aneuploidy. The extra X chromosome can come from the paternal or maternal side. If the problem arises on the maternal side, the offspring will get both X chromosomes from the mother. If the problem comes from the paternal side, the offspring will inherit an X chromosome from the mother and both an X and Y chromosome from the father. Either of these errors will result in the (47, XXY) genotype that causes Klinefelter syndrome. Figure 2 demonstrates the nondisjunction that can occur in both maternal and paternal germ cells. On the paternal side, the mistake can only occur during meiosis I. On the maternal side, the nondisjunction can occur in meiosis I or meiosis II. If the nondisjunction occurs in meiosis I, two of the four resulting haploid cells will potentially have the extra X chromosome that results in Klinefelter syndrome. If the nondisjunction occurs in meiosis II, two of the resulting cells will be normal and two will have an incorrect number of chromosomes. However, only one of the abnormal chromosomes potentially has the extra X chromosome. The most common nondisjunction occurs during meiosis I (Lanfranco, Kamischke, Zitzmann & Nieschlag, 2004). Figure 2. Chart explaining various methods of nondisjunction in maternal and paternal germ cell (Lanfranco, 2004).

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A male who presents a case with a X-chromosome diosomy, (47, XXY) shows many levels of symptoms that are directly related to testosterone deficiencies. Individuals with the syndrome can receive treatment at an early age into adulthood. Treatments target prepubescent and pubescent periods when young males are developing secondary sex characteristics. Infertility issues rise from this syndrome that are expressed differently in mosaic and non-mosaic males. In mosaic males there is a low number of viable spermatogonia; on the other hand, non-mosaic males are affected and result in sterility. Sterility is due to difficulties that are presented to spermatognia when entering meiosis, instead spermatozoa during puberty undergo apoptosis (Fullerton, Hamilton & Maheshwari, 2010). The addition of an extra X chromosome is sought to be the causing agent for infertility by inducing germ cell to degrade. =====


 *  Physiological Management and Treatments **

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Testosterone supplements can be transdermal, intramuscular, subcutaneous implant pellets, oral medications, and topical gel treatments that introduce androgen hormones into testosterone deficient males (WebMD,2005). The following are some of the common pharmacological androgen supplements: =====
 * =====**Oral** ===== || =====**Intramuscular** ===== || =====**Transdermal** ===== || =====**Buccal** ===== || =====**Pellet Implan**t ===== ||
 * =====<span style="font-family: Arial,Helvetica,sans-serif;">Android ===== || =====<span style="font-family: Arial,Helvetica,sans-serif;">Testosterone cypionate ===== || =====<span style="font-family: Arial,Helvetica,sans-serif;">AndroGel ===== || =====<span style="font-family: Arial,Helvetica,sans-serif;">Straint ===== || =====<span style="font-family: Arial,Helvetica,sans-serif;">Testopel ===== ||
 * =====<span style="font-family: Arial,Helvetica,sans-serif;">Methitest ===== || =====<span style="font-family: Arial,Helvetica,sans-serif;">Testosterone enanthate ===== || =====<span style="font-family: Arial,Helvetica,sans-serif;">Testim ===== || =====<span style="font-family: Arial,Helvetica,sans-serif;">Tesosterone ===== ||
 * =====<span style="font-family: Arial,Helvetica,sans-serif;">Androxy ===== || =====<span style="font-family: Arial,Helvetica,sans-serif;">Delatestryl ===== || =====<span style="font-family: Arial,Helvetica,sans-serif;">Fortesta ===== ||
 * =====<span style="font-family: Arial,Helvetica,sans-serif;">Testred ===== || =====<span style="font-family: Arial,Helvetica,sans-serif;">Depo-Testosterone ===== || =====<span style="font-family: Arial,Helvetica,sans-serif;">Axiron ===== ||
 * =====<span style="font-family: Arial,Helvetica,sans-serif;">Methyltestosterone ===== ||


 * =====<span style="font-family: Arial,Helvetica,sans-serif;">Poor pubescent development =====
 * =====<span style="font-family: Arial,Helvetica,sans-serif;">Low testosterone =====
 * =====<span style="font-family: Arial,Helvetica,sans-serif;">Lack of muscular tone =====
 * =====<span style="font-family: Arial,Helvetica,sans-serif;">Lack facial and body hair =====
 * =====<span style="font-family: Arial,Helvetica,sans-serif;">Self-esteem =====
 * =====<span style="font-family: Arial,Helvetica,sans-serif;">Underdeveloped sexual organs during puberty =====

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<span style="font-family: Arial,Helvetica,sans-serif;">Figure 3. Chart of testosterone influences on pubescent males, and other important developmental events that are testosterone dependent (Mayo Foundation, 2011). =====

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<span style="font-family: Arial,Helvetica,sans-serif;">Although there are many synthetic types of the hormone testosterone, one major problem arises when Klinefelter syndrome individuals consider offspring. Due to underdeveloped testes and low number of spermatogonia, individuals affected are not able to produce sperm gametes in large quantities causing reproduction difficulties. Infertility is treated by a microsurgical procedure called testicular sperm extraction (TESE). This is one of the latest fertility developments made in the past decade (Paduch, Fine , Bolyakov & Kiper , 2008). Fifty percent of Klinfelter syndrome males have been allowed to reproduce through Artificial Reproductive Technologies (ART) that include TESE procedures, and newly retrieved sperm for artificial insemination (AI). Although AI is common and a less expensive alternative, TESE procedures have successful rates of ovum fertilization. =====

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<span style="font-family: Arial,Helvetica,sans-serif;"> The TESE microsurgical procedure involves the surgical biopsy of testicular tissue. Urology microsurgeons preform the procedure on the same day that an ovum is extracted from the female partner. The procedure consists of a medial scrotal incision to expose the testes (Marconi, Keudel, Bergmann, Steger, H-C Shuppe & Wolfgang, 2012). Micro epididymal sperm extraction and micro biopsies of testicular tissue, figure 4 (Testicular biopsy, 2012), are taken through careful procedures to avoid vascular tissue disruption. Testicular biopsies are then studied in search of spermatogonia. If the samples do not contain spermatozoa, then a surgical microscope is used to find seminiferous tubules where vial spermatozoa can be found and extracted. Up until the late 1990's males with Klinfelter syndrome were considered as infertile individuals due to the notion of sterility, but ART have shown that affected individuals do produce viable gametes. Figure 5 shows a micrograph of seminiferous tubules where potential vial spermatozoa can be found (TESE,2012). Once spermatozoa has been extracted, then //in vitro// fertilization (IVF) of an ovum can be conducted. =====

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<span style="font-family: Arial,Helvetica,sans-serif;">Figure 5. Depiction of microsurgical sperm extraction in the midline incision of scrotal tissue with dilated seminiferous tubules. Magnification 25x (TESE,2012). =====

__**References**__
Anagnostopoulos, A. K., Kolialexi, A., Maurou, A., Vougas, K., Papantoniou, N., Antsaklis, A., Kanavakis, E., Fountoulakis, M., & Tsangaris, G. "Proteomic Analysis of Amniotic Fluid in Pregnancies with Klinefelter Syndrome Foetuses." //Proteomics// (2009). Retrieved from http://www.sciencedirect.com/science/article/pii/S1874391909003911

Bock, R. (1993). Understanding klinefelter syndrome a guide for xxy males and their families. //National Institutes of Health Pub.//, (93-3202), Retrieved from http://www.nichd.nih.gov/publications/pubs/klinefelter.acfm

Eaker, S., Pyle, A., Cobb, J., & Handel, M. (2001). Evidence for meiotic spindle checkpoint from analysis of spermatocytes from robertsonian-chromosome heterozygous mice. //Journal of Cell Science//, (114), 2853-2965. Retrieved from http://jcs.biologists.org/content/114/16/2953.full.pdf

Fullerton, G., Hamilton, M., & Maheshwari, A. (2010). Should non-mosaic klinefelter syndrome men be labelled as infertile in 2009. //Human Reproduction//, //25//(3), 588-597. Retrieved from http://humrep.oxfordjournals.org/content/early/2010/01/19/humrep.dep431.full.pdf.html

<span style="font-family: Arial,Helvetica,sans-serif; font-size: 90%;">//Klinefelter syndrome//. The University of Utah. (2012). Retrieved from []

<span style="font-family: Arial,Helvetica,sans-serif; font-size: 90%;">//Klinefelter Syndrome//. (2008). Retrieved from http://www.medicinenet.com/klinefelter_syndrome/article.htm Lanfranco, F., Kamischke, A., Zitzmann, M., & Nieschlag, E. (2004). Klinefelter’s syndrome. //Lancet//, (364), 273-83. Retrieved from http://www.sciencedirect.com/science/article/pii/S0140673604166786

//Learning about Klinefelter Syndrome//. (2001). Retrieved from http://www.genome.gov/19519068

Mayo Foundation. (2011). //Influence of testosterone.// Retrieved from http://scipwn.files.wordpress.com/2011/02/testosterone.jpg

Marconi, M., Keudel, A., Bergmann, M., Steger, K., H-C Shuppe, & Wolfgang, W. (2012). Combined trifocal and microsurgical testicular sperm extraction is the best technique for testicular sperm retrieval in “low-chance” nonobstructive azoospermia. //European Urology//, Retrieved from http://www.europeanurology.com/article/S0302-2838(12)00314-4/fulltext

Paduch, D., Fine, R.G., Bolyakov, A., & Kiper, J. (2008). New concepts in Klinefelter syndrome. //Current Opinion in Urology//, //18//, 621-627. Retrieved from http://47xxy.com/Hermes/New concepts in Klinefelter syndrome.pdf //Tese//. (2012). Retrieved from http://europeanurology.com/uploads/eur_articles/S0302-2838(12)00314-4/assets/gr2.jpg //Testicular biopsoy//. (2012). Retrieved from http://www.europeanurology.com/uploads/eur_articles/S0302-2838(12)00314-4/assets/gr3.jpg

WebMD. (2005). //Klinefelter's syndrome drugs//. Retrieved from http://www.webmd.com/drugs/condition-2945-Klinefelter's+Syndrome.aspx?diseaseid=2945&diseasename=Klinefelter's+Syndrome&source=0