What is Klinefelter syndrome?
In 1942, Harry Klinefelter, Fuller Albright, and their coworkers at the Massachusetts General Hospital published a report about 9 men who had enlarged breasts, sparse facial and body hair, small testes, and the inability to produce sperm. This combination of features has come to be recognized as Klinefelter syndrome.
What causes Klinefelter syndrome?
Klinefelter syndrome is caused by the presence of an extra sex chromosome. Males with the syndrome have a sex chromosome composition of XXY instead of the usual XY male sex chromosome complement.
What is XXY?
Chromosomes are carriers of DNA, the hereditary material. The chromosomes are visible under an ordinary light microscope.
Men and women usually have 2 sex chromosomes. Women inherit 2 X chromosomes, one from each parent. Men inherit an X chromosome from their mother and a Y chromosome from their father.
Males with Klinefelter syndrome usually have an additional X chromosome for a total of three sex chromosomes -- two X chromosomes and one Y chromosome.
What causes XXY?
XXY is caused by a biological accident during a process called meiosis. Meiosis is a process experienced by all cells which are destined to develop into sperm or eggs. In this process, the 46 chromosomes in the cell divide to make two new cells with 23 chromosomes each. Before meiosis is completed, however, chromosomes pair with their corresponding chromosomes and exchange bits of genetic material. In women, the X chromosomes from each parent pair, and in men, the X and Y chromosomes pair. After the exchange, the chromosomes separate, and meiosis continues. In some cases, the two X chromosomes or the X and Y chromosomes fail to pair and fail to exchange genetic material. Occasionally, this results in their moving independently to the same cell, producing either an egg with two Xs, or a sperm having both an X and a Y chromosome. When a sperm having both an X and a Y chromosome fertilizes an egg having a single X chromosome, or a normal sperm bearing a Y chromosome fertilizes an egg having two X chromosomes, an XXY male is conceived.
About 50 percent of the time, the extra chromosome comes from the father and the other 50 percent of the time, it comes from the mother. Older mothers have a slightly increased risk of having a boy with XXY.
How common is Klinefelter syndrome?
In the early 1970s, it was found that the XXY was one of the most common chromosomal abnormalities, occurring as frequently as 1 in 500 male births. [On a world-wide basis, the rate of birth of XXY/variant is 1:700 to 1000 live male births.]
Who are XXY males?
Although XXY is common, the syndrome itself -- the set of signs and symptoms that may result from having the extra chromosome -- is quite uncommon. Many men with XXY live out their lives without ever suspecting that they have an additional chromosome. For this reason, some experts prefer to describe boys and men with the extra chromosome as "XXY males" rather than Klinefelter syndrome males. [All XXY males have Klinefelter Syndrome.]
What problems do XXY males have?
In addition to occasional breast enlargement, lack of facial and body hair, and a rounded body type, XXY males are more likely than other males to be overweight, and tend to be taller than their fathers and brothers.
A far more serious problem is one that is not always readily apparent. Although XXY males are not usually mentally retarded, most have some degree of language impairment. As children, they often learn to speak much later than do other children and may have difficulty learning to read and write. And while they eventually do learn to speak and converse normally, the majority tend to have some degree of difficulty with language throughout their lives.
If untreated, this language impairment can lead to school failure and its attendant loss of self esteem. Fortunately, however, this language disability usually can be compensated for. Chances for success are greatest if treatment for the language difficulty is begun in early childhood.
How is the diagnosis of XXY made?
A study of the person's chromosomes is done to make the diagnosis of XXY. The test is commonly called a karyotype (a standard layout of the chromosomes).
To perform a karyotype of the blood cells, a small blood sample is drawn. White blood cells are separated from the sample, mixed with a tissue culture medium, incubated, and checked for chromosomal abnormalities, such as an extra X chromosome.
When is the diagnosis of XXY typically made?
Because they often don't appear any different from anyone else, many XXY males never learn of their extra chromosome. However, if they are diagnosed, this most likely occurs before birth, early childhood, adolescence, or in adulthood (as a result of testing for infertility).
Before birth: In recent years, many XXY males have been diagnosed before birth through amniocentesis or chorionic villus sampling (CVS). In amniocentesis, a sample of the fluid surrounding the fetus is withdrawn. Fetal cells in the fluid are then examined for chromosomal abnormalities. CVS is similar to amniocentesis, except that the procedure is done in the first trimester of the pregnancy and the fetal cells needed for examination are taken from the placenta. Neither procedure is used routinely except when there is a family history of genetic defects, the pregnant woman is older than 35, or when other medical indications are present.
Early childhood: The next most likely opportunity for diagnosis is when the child begins school. A physician may suspect a boy is an XXY male if he is delayed in learning to talk and has difficulty with reading and writing. XXY boys may also be tall and thin and somewhat passive and shy. Again, however, there are no guarantees. Some of the boys who fit this description will have the XXY chromosome count, but many others will not.
Adolescence: A few XXY males are diagnosed at adolescence, when excessive breast development compels them to seek medical attention. Like some chromosomally normal males, many XXY males undergo slight breast enlargement at puberty. Of these, only a fraction of XXY males develop breasts large enough to embarrass them.
Adulthood: A diagnosis of XXY in adulthood is usually the result of testing for infertility. At this time, an examining physician may note the undersized testes which are characteristic of an XXY male. In addition to infertility tests, the physician may order tests to detect increased levels of hormones known as gonadotropins, which are common in XXY males.
What information concerning an XXY boy should parents share with others?
Expectant parents awaiting the arrival of their XXY baby have difficult choices to make: whom to tell and how much to tell about their son's extra chromosome.
The go-slowly school of thought holds that the best course is to go slowly, waiting at least a year before telling anyone, grandparents included, about the child's extra chromosome. The idea is that some people are frightened by the diagnosis, and their fears will color their perceptions of the child. For example, some people may confuse the term Klinefelter syndrome with Down syndrome (a different chromosomal condition which is associated with mental retardation).
The up-front school of thought prefers to share the diagnosis early. Some parents have found that grandparents, aunts, uncles, and the extended family are more supportive when they are given accurate information.
What should an XXY boy be told?
Another important decision parents must make is when to tell their son about his diagnosis. Some experts recommend telling the child early. When the truth is withheld, children often suspect that their parents are hiding something and may imagine a condition that is worse than their actual diagnosis. This school of thought maintains that by the time he is 10 or 11 years old, the child can be told that his cells differ slightly from those of other people. Soon after, he can be filled in on the details: that the cell difference is due to an additional X chromosome, which is responsible for his undersized testes and any reading difficulties he may have. At this time, the child can be reassured that he does not have a disease and will not become sick. The child should also be told that some people may misunderstand this information and that he should exercise discretion in sharing it with others.
By about 12, depending on the boy's emotional maturity, he can be told that he will most probably be infertile. Parents should stress that neither the X chromosome nor the infertility associated with it mean that he is in any way less masculine than other males his age. The child's parents or his physician can explain that although he may not be able to biologically father a baby, he can consider adopting one. Parents may also need to reassure an XXY boy that his small testes will in no way interfere with his ability to have a normal sex life.
Adherents of this school of thought believe that learning about possible infertility in such a gradual manner will be less of a shock than finding out about it all at once, such as late in the teen years.
Conversely, other experts believe that withholding the information does not appear to do any harm. Instead, telling an XXY boy about his extra chromosome too early may have some unpleasant consequences. An 11 or 12-year-old, for example, may associate infertility with sexual disorders and other concepts he may not yet understand.
Moreover, children, when making friends, tend to share secrets. But childhood friendships may be fleeting, and early confidences are sometimes betrayed. A malicious or thoughtless child may tell all the neighborhood children that his former companion is a "freak" because he has an extra chromosome. For these reasons, some experts believe the best time to reveal the information may be mid-to-late adolescence, when an XXY male is old enough to understand his condition and better able to decide with whom he wishes to share this knowledge.
What are XXY boys like in childhood?
XXY babies differ little from other children their age. They tend to start life as what many parents call "good" babies -- quiet, undemanding, and perhaps even a little passive. As toddlers, they may be somewhat shy and reserved. They usually learn to walk later than most other children.
XXY boys may have delays in learning to speak. The language delays for some boys may be severe, with the child not fully learning to talk until about age 5. Others may learn to speak at a normal rate, and not meet with any problems until they begin school, where they may experience reading difficulties. A few may not have any problems at all in learning to speak or read.
XXY males usually have difficulty with expressive language -- the ability to put thoughts, ideas, and emotions into words. In contrast, their faculty for receptive language -- understanding what is said -- is close to normal.
XXY boys, like other language-disabled children, may need help with social skills. Language is essential not only for learning the school curriculum, but also for building social relationships. By talking and listening, children make friends in the process, sharing information, attitudes, and beliefs. Through language, they also learn how to behave not just in the schoolroom, but also on the playground. If their sons' language disability seems to prevent them from fitting in socially, the parents of XXY boys may want to ask school officials about a social skills training program.
XXY boys tend to retain the same temperament and disposition they first displayed as infants and toddlers. As a group, they tend to be shy, somewhat passive, and unlikely to take a leadership role. Although they do make friends with other children, they tend to have only a few friends at a time. They also tend as a group to be cooperative and eager to please.
How can language problems be detected early?
The parents of XXY babies can compensate for their children's language disability by providing special help in language development, beginning at an early age. However, there is no easy formula to meet the language needs of all XXY boys. Like everyone else, XXY males are unique individuals. A few may not have any trouble learning to read and write, while the rest may have language impairments ranging from mild to severe.
If their son's speech seems to be lagging behind that of other children, parents should ask their child's pediatrician for a referral to a speech pathologist for further testing. A speech pathologist specializes in the disorders of voice, speech, and language.
Parents should also pay particular attention to their children's hearing. Like other small children, XXY infants and toddlers may suffer from frequent ear infections. With any child, such infections may impair hearing and delay the acquisition of language. Such a hearing impairment may be a further setback for an XXY child who is already having language difficulties.
What guidelines can be used to detect language problems?
Shortly after the first birthday, children should be able to make their wishes known with simple one-word utterances. For example, a child may say "milk" to mean "I want more milk." Gradually, children begin to combine words to produce two-word sentences, such as "More milk." By age three, most children use an average of about four words per sentence. If your child is not communicating effectively with single words by 18 to 24 months, then you should seek a consultation with a speech and language pathologist.
How do XXY boys perform at school?
Although there are exceptions, XXY boys are usually well behaved in the classroom. Most are shy, quiet, and eager to please the teacher. But when faced with material they find difficult, these boys tend to withdraw into quiet daydreaming. Teachers sometimes fail to realize they have a language problem, and dismiss them as lazy, saying they could do the work if they would only try. Many become so quiet that teachers forget they're even in the room. As a result, they fall farther and farther behind, and eventually may be held back a grade.
How can educational laws help an XXY boy at school?
XXY boys do best in small, uncrowded classrooms where teachers can give them a lot of individual attention. Parents who can meet the expenses may consider sending their sons to a private school offering special educational services. Parents who cannot afford private schools should become familiar with Public Law 94-142, the Education of the Handicapped Act -- now called the Individuals with Disabilities Education Act. This law, adopted by Congress in 1975, states that all children with disabilities have a right to a free, appropriate public education. The law cannot ensure that every child who needs special educational services will automatically get them. But the law does allow parents to take action when they suspect their child has a learning disability. Chances for success are greatest for parents who are well informed and work cooperatively with the schools to plan educational and related service programs for their sons.
Parents may also wish to contact their local and state boards of education for information on how the law has been implemented in their area. In addition, local educational groups may be able to provide useful information on working with school systems. Parents should also consider taking a course in educational advocacy. The local public school system, the state board of education, or local parent groups may be able to tell parents where they can enroll in such a course.
How can educational laws help a younger XXY boy?
The chances for minimizing the impact of a learning disability are greatest in early childhood. Public Law 99-457 is an amendment to Public Law 94-142 that assists states in providing special educational services for infants, toddlers, and preschoolers. Eligibility requirements and entrance procedures vary from state to state.
How can an XXY boy be helped to learn?
Because XXY boys often have decreased immediate auditory recall, they have trouble remembering what they have just heard. Parents and teachers can help them remember by approaching memory through visual channels. Illustrating words with pictures may help. Gesturing is another useful technique. For example, a teacher might accompany the word "yes" with a nod of the head. Similarly, shaking the head from side to side is the universal gesture for "no." Other useful gestures include waving goodbye, showing the child an upraised palm to indicate "stop," and holding the arms outstretched to mean "so big."
XXY males frequently have trouble finding the right word to describe an object or a situation. Parents and teachers can help them build vocabulary through a variety of techniques. One way is to provide them with synonyms, such as pointing out that a car is also called an automobile. Another important teaching tool is categorizing -- showing the child that an item belongs to a larger class of items. With this technique, a child could be told that cars, buses, trucks, and bicycles are all vehicles, machines that carry people and things from place to place.
Because XXY boys have difficulty expressing themselves, they may do poorly on essay-style test questions. Multiple choice questions can give teachers a better idea of what an XXY child has learned and prove less stressful for him as well. Similarly, rather than asking an open-ended question, parents and teachers may wish to present alternatives. Instead of asking "What would you like to do now?" they may wish to offer a choice: "Would you rather work on your spelling or work on your math?"
Parents and teachers can help XXY boys develop the ability to express themselves through solicited dialogue by engaging them in conversation through a series of questions. The same technique can be used to encourage the child to develop his narrative (storytelling) abilities. For example, a parent might begin by asking a child what he did at recess that day, and by following up with questions that prompt the child to talk about his activities: "Did you go down the slide? Were you afraid when you climbed all the way to the top of the ladder? And then what? Did you go on the seesaw? Who sat on the other end?"
Parents can also help XXY boys develop their expressive language abilities simply by providing good examples. Through a technique known as modeling, they can help organize their children's thoughts and provide them with examples of how to express themselves. For instance, if a younger child indicates that he wants a toy fire engine by pointing at it and grunting, the parent could hand it to him while saying: "Here you are. This is a fire engine." Similarly, if an older child asks "Are we going to put the stuff in the thing?" the parent might reply "Yes, we're going to put the oranges in the shopping cart."
Research indicates that XXY boys may do poorly in an open classroom situation and seem to prefer a structured, tightly organized environment centered around familiar routines. Teachers can reduce the distraction level for these students by placing them in front row seats. Teachers also should present information slowly and repeat key points several times, if necessary. XXY boys should not be given tasks that have many small steps. Rather, each step should be presented individually. On completion, the child may then be asked to work on the next item in the series.
XXY boys may withdraw from material they find difficult and retreat into day dreaming. A teacher or parent should gently regain the child's attention and help him to focus again on the task at hand. Similarly, XXY boys may have difficulty putting one task aside and beginning another one.
What are XXY boys like in adolescence?
In general, XXY boys enter puberty normally, without any delay of physical maturity. But as puberty progresses, they fail to keep pace with other males. In chromosomally normal teenaged boys, the testes gradually increase in size, from an initial volume of about 2 ml, to about 15 ml. In XXY males, while the penis is usually of normal size, the testes remain at 2 ml, and cannot produce sufficient quantities of the male hormone, testosterone. As a result, many XXY adolescents, although taller than average, may not be as strong as other teenaged boys, and may lack facial or body hair.
As they enter puberty, many boys will undergo slight breast enlargement. For most teenaged males, this condition, known as gynecomastia, tends to disappear in a short time. About one-third of XXY boys develop enlarged breasts in early adolescence, slightly more than do chromosomally normal boys. In XXY boys, this condition may be permanent. However, only about 10 percent of XXY males have breast enlargement great enough to require surgery.
Most XXY adolescents benefit from receiving an injection of testosterone every 2 weeks, beginning at puberty. The hormone increases strength and brings on a more muscular, masculine appearance. (See Testosterone Treatment below.)
Adolescence and the high school years can be difficult for XXY boys and their families, particularly in neighborhoods and schools where the emphasis is on athletic ability and physical prowess. Lack of strength and agility, combined with a history of learning disabilities, may damage self-esteem. Unsympathetic peers, too, may sometimes make matters worse through teasing or ridicule. While XXY males share many characteristics, they cannot be pigeonholed into rigid categories. Several have played football, and one, in particular, is an excellent tennis player.
The damage to self esteem may be more severe in XXY teenagers who are diagnosed in early or late adolescence. Teachers and even parents may have dismissed their learning difficulties as laziness. Lack of athletic prowess and their inability to use language properly in social settings may have resulted in isolating these teens from their peers. Some may react by sliding quietly into depression and withdrawing from contact with other people. Others may try to find acceptance in a dangerous crowd.
For these reasons, XXY males who are diagnosed as teenagers may need psychological counseling as well as help in overcoming their learning disabilities. Assistance with learning disabilities is available through public school systems for XXY males high-school age and under. Referrals to qualified mental health specialists can be obtained from family physicians.
Is testosterone treatment advisable for XXY males?
Ideally, XXY males should begin testosterone treatment as they enter puberty. XXY males diagnosed in adulthood are also likely to benefit from the hormone. A regular schedule of testosterone injections increases strength and muscle size, and promotes the growth of facial and body hair.
Testosterone injections often induce beneficial psychological changes as well. As they begin to develop a more masculine appearance, the self-confidence of XXY males tends to increase. Many become more energetic and stop having sudden, angry mood changes. What is not clear is whether these psychological changes are a direct result of the testosterone treatment or are a side benefit of the increased self confidence that the treatment may bring. As a group, XXY boys tend to suffer from depression, principally because of their scholastic difficulties and problems fitting in with other males their age. Sudden, angry mood changes are typical of depressed people.
Other benefits of testosterone treatment may include a decreased need for sleep, an enhanced ability to concentrate, and improved relations with others. However, in order to benefit from the treatment, an XXY male must decide on his own that he is ready to commit to a regular schedule of injections.
Sometimes, younger adolescents, who may be somewhat immature, seem not quite ready to take the shots. It is an inconvenience, and many don't like needles. Most physicians do not push the young men to take the injections. Instead, they usually recommend informing XXY adolescents and their parents about the benefits of testosterone injections and letting them take as much time as they need to make their decision.
Individuals can respond to testosterone treatment in different ways. Although the majority of XXY males ultimately benefit from testosterone, a few do not. To ensure that the injections will provide the maximum benefit, XXY males who are ready to begin testosterone injections should consult a qualified endocrinologist (a medical doctor who is a specialist on hormones) who has experience treating XXY males.
What are the possible side effects of testosterone treatment?
Side effects of testosterone injections are few. Some individuals may develop a minor allergic reaction at the injection site, resulting in an itchy welt resembling a mosquito bite. Applying a non- prescription hydrocortisone cream to the area will reduce swelling and itching.
Testosterone injections may also result in a condition known as benign prostatic hyperplasia (BPH). This condition is also common in chromosomally normal males, affecting more than 50 percent of men in their sixties, and as many as 90 percent in their seventies and eighties. In XXY males receiving testosterone injections, this condition may begin sometime after age 40. In BPH, the prostate increases in size, sometimes squeezing the bladder and urethra and causing difficulty urinating, "dribbling" after urination, and the need to urinate frequently. XXY males receiving testosterone injections should consult their physicians about a regular schedule of prostate examinations.
Are there variations of the XXY chromosome complement?
Variations of the XXY chromosome count can occur. The most common is XY/XXY mosaicism in which some cells have the additional X chromosome and others do not. The percentage of cells containing the extra chromosome varies from case to case. In some instances, XY/XXY mosaics may have enough normally functioning cells in the testes to allow them to father children.
Males with 2, 3, or 4 extra X chromosomes have also been reported in the medical literature -- XXY, XXXY, or XXXXY. In these individuals, the features of Klinefelter syndrome may be exaggerated, with a low IQ or moderate to severe mental retardation. In rare instances, an individual may possess both an additional X and an additional Y chromosome.
What is the sexual behavior of XXY boys?
There is no evidence that XXY males are any more inclined toward homosexuality than are other men. The only significant sexual difference between XXY men and teenagers and other males their age is that the XXY males may have less interest in sex. However, regular injections of the male sex hormone testosterone can bring sex drive up to normal levels.
In some cases, testosterone injections lead to a false sense of security. After receiving the hormone for a time, XXY males may conclude they have derived as much benefit from it as possible and discontinue the injections. But when they do, their interest in sex almost invariably diminishes until they resume the injections.
What is the fertility of XXY males?
The vast majority of XXY males do not produce enough sperm to allow them to become biological fathers. If these men and their wives wish to become parents, they should seek counseling from their family physician regarding infertility and adoption.
No XXY male should automatically assume he is infertile without further testing. In a very small number of cases, XXY males have been able to father children. In addition, a few individuals who believe themselves to be XXY males may actually be XY/XXY mosaics. Along with having cells with the XXY chromosome count, these males may also have cells with the normal XY chromosome count. If the number of XY cells in the testes is great enough, the individual should be able to father children. Karyotyping, the method traditionally used to identify an individual's chromosome count, may sometimes fail to identify XY/ XXY mosaics. For this reason, a karyotype should never be used to predict whether an individual will be infertile or not. [All XXY males are infertile.]
Are there special health concerns for XXY males?
Compared with other males, XXY males have a slightly increased risk of autoimmune disorders. In this group of diseases, the immune system, for unknown reasons, attacks the body's organs or tissues. The most well known of these diseases are type I (insulin dependent) diabetes, autoimmune thyroiditis, and systemic lupus erythematosus. Most of these conditions can be treated with medication. XXY males with enlarged breasts have the same risk of breast cancer as do women -- roughly 50 times the risk XY males have. For this reason, these XXY adolescents and men need to practice regular breast self examination. XXY males may also wish to consult their physicians about the need for more thorough breast examinations by medical professionals.
XXY males who do not receive testosterone injections may have an increased risk of developing osteoporosis in later life. In this condition, which usually afflicts women after the age of menopause, the bones lose calcium, becoming brittle and more likely to break. [Of all people who have breast cancer, 1% are male and of those males, 0.58% have Klinefelter Syndrome.]
What are XXY males like in adulthood?
Relatively little is known about XXY adults. Studies in the U.S. have focused largely on XXY males identified in infancy from large random samples. Only a few of these individuals have reached adulthood; most are still in adolescence.
Comparatively few studies of XXY males diagnosed in adulthood have been conducted. By and large, the men who took part in these studies were not selected at random but identified by a particular characteristic, such as height. For this reason, it is not known whether these individuals are truly representative of XXY men as a whole or simply represent a particular segment.
One study found a group of XXY males diagnosed between the ages of 27 and 37 to have suffered a number of setbacks in comparison to a similar group of XY males. The XXY men were more likely to have had histories of scholastic failure, depression, and other psychological problems, and to lack energy and enthusiasm. But by the time the XXY men had reached their forties, most had surmounted their problems. The majority said that their energy and activity levels had increased, they were more productive on the job, and their relationships with other people had improved. In fact, the only difference between the XY males and the XXY males was that the latter were less likely to have been married.
That these men eventually overcame their troubled pasts is encouraging for all XXY males and particularly encouraging for those diagnosed in childhood. Had they received counseling, support, and testosterone treatments beginning in childhood, these men might have avoided the difficulties of their twenties and thirties.
Although a supportive environment through childhood and adolescence appears to offer the greatest chance for a well-adjusted adulthood, it is not too late for XXY men diagnosed as adults to seek help. Research has shown that testosterone injections, begun in adulthood, can be beneficial. Psychological counseling also offers the best hope of overcoming depression and other psychological problems. For referrals to endocrinologists qualified to administer testosterone or to mental health specialists, XXY men should consult their physicians.
This article is based upon information from NICHD (a part of the NIH), the unrivaled experience of Dr. Arthur Robinson at the University of Colorado Medical School in Denver, and that of the MedicineNet author.
Klinefelter Syndrome At A Glance
Klinefelter syndrome is a chromosome condition in males.
There are 47 chromosomes including XXY sex chromosomes (instead of 46 chromosomes including XY sex chromosomes).
One in 500 males has Klinefelter syndrome.
Patients with XXY tend to be taller than their fathers and brothers.
Boys with XXY often have language difficulties.
Adult males with XXY may have enlarged breasts, sparse facial and body hair, small testes, and the inability to produce sperm.
A chromosome study of white blood cells or fetal cells can be used to diagnosis the XXY chromosome constitution.
Males with Klinefelter syndrome can greatly benefit from the support of family, friends, teachers, and medical professionals.
Chromosomes DefinedY chromosome:
The sex chromosome found together with an X chromosome in most normal males. Once thought to be a genetic wasteland, the Y now is known to contain at least 20 genes, some of them unique to the Y including the male-determining gene and male fitness genes that are active only in the testis and are thought responsible for the formation of sperm. Other genes on the Y have counterparts on the X chromosome, are active in many body tissues and play crucial "housekeeping" roles with the cell.
As of the year 2000, a number of specific genes have been Y-linked including:
ASMTY (which stands for acetylserotonin methyltransferase),
TSPY (testis-specific protein),
IL3RAY (interleukin-3 receptor),
SRY (sex-determining region),
TDF (testis determining factor),
ZFY (zinc finger protein), PRKY (protein kinase, Y-linked),
AMGL (amelogenin),
CSF2RY (granulocyte-macrophage colony-stimulating factor receptor, alpha subunit on the Y chromosome),
ANT3Y (adenine nucleotide translocator-3 on the Y),
AZF2 (azoospermia factor 2),
BPY2 (basic protein on the Y chromosome),
AZF1 (azoospermia factor 1),
DAZ (deleted in azoospermia),
RBM1 (RNA binding motif protein, Y chromosome, family 1, member A1),
RBM2 (RNA binding motif protein 2) and
UTY (ubiquitously transcribed TPR gene on Y chromosome).
X chromosome:
The sex chromosome found twice in normal females and singly, along with a Y chromosome, in normal males.
The complete chromosome complement (consisting of 46 chromosomes including the two sex chromosomes) is thus conventionally written as 46,XX for chromosomally normal females and 46,XY for chromosomally normal males.
[Indicates comments provided by Bill Bucar]
Klinefelter's Syndrome from Lycoming College
In 1942, Dr. Harry Klinefelter and his associates at the Massachusetts General Hospital in Boston published a report about male patients with enlarged breasts, sparce facial and body hair, small testes, and the inability to produce sperm (Bellenir, 1996). By the 1950's, this condition, termed Klinefelter's Syndrome, was discovered to be the result of genetic misfunction. It is only found in males and is caused by sex chromosome aneuploidy (Orbis Broadcast Group, 1998). This
trisomal karyotype, 47, XXY, is not all that uncommon a condition. Estimates of the appearance of this karyotype in the world population range from one in five hundred to one in one thousand male births, making it one of the most common genetic abnormalities known. A more localized study conducted in Denmark, population five million, showed an occurrence of one in seven hundred male births (Turner Center).
However, this statistic is somewhat misleading due to the fact that not all those who possess the 47, XXY karyotype exhibit the syndrome. In fact, most 47, XXY men go through life never knowing about their odd abundance of sex chromosomes. Therefore, a better name for the particular karyotype might be 47, XXY males, with the name Klinefelter's Syndrome specifically applying to those with observed symptoms. According to Tournaye et. al. the incidence of Klinefelter Syndrome in the general population is 0.1%.
There is a wide variety of symptoms of which any number may be expressed with varying severity. They include lack of secondary sexual characteristics, development of female characteristics, infertility, language impairment, and mental retardation.
Because Klinefelter's Syndrome is a sexual disorder, its effects are not usually noticed in individuals until the onset of puberty. At that time, the development of secondary sexual characteristics that normal 46, XY boys experience is lacking. The testicles remain small and very little facial and body hair grows (both are characteristics originally observed by Dr. Klinefelter in his patients). These symptoms along with reduced muscular development and noticeable breast tissue development are the result of testosterone deficiency. In Klinefelter's individuals, inadequate quantities of testosterone are produced when luteinizing hormone (LH) from the anterior pituitary gland binds to the dysfunctional Leydig cells in the testes (Tournaye et. al., 1996).
Without the testosterone, the normal changes in the body that are supposed to occur are not stimulated. Follicular stimulating hormone (FSH), another hormone from the anterior pituitary is also rendered ineffective in Klinefelter's patients, because its receptors, Sertoli cells, are unable to produce much sperm (Slywka, 1994). This leads to the most severe and widespread symptom of the syndrome--infertility. According to Tournaye et. al., the incidence of Klinefelter Syndrome
is 3.1% in the infertile male population. At this point it is important to note the other problem with low testosterone levels. Because this system works in a negative feedback manner, levels of LH
and FSH remain high if no testosterone is produced, resulting in the occasional development of female characteristics such as breast tissue formation, called gynecomastia, and a rounded body type (Slywka, 1994). Some other, more minor symptoms include a tendency to be overweight and tall, specifically, taller than brothers and father.
Often, some type of language impairment goes along with Klinefelter's. It can bemanifested by a lack of spoken language, a depressed vocabulary, a lack of verbal organization, poor word retrieval, or any combination of these (Lucker-Lazerson, 1997). These are all considered expressive language disorders and children and adults with them may not speak clearly, use vague language, and appear to be disorganized when talking. When the poor verbal skills are combined with the poor coordination that stems from reduced muscular development and increased height, individuals will naturally be shy and lacking in self esteem. Obviously, the language problems can cause a serious learning deficit and the appearance of subpar intelligence. However, intelligence scores of affected males usually fall within normal limits, only tending to reflect lower verbal than nonverbal skills (Utah Department of Health, 1993). Because Klinefelter Syndrome is often not diagnosed, it is difficult to estimate the frequency and severity of intellectual problems.
Mental retardation can be caused by Klinefelter Syndrome, but not in the usual 47, XXY karyotype. Instead, it results from multiple aneuploidies such as 48, XXXY; 48, XXYY; and 49, XXXXY (Robinson et. al., 1994). These individuals generally demonstrate more cognitive and
behavioral problems, and therefore, can not be considered simultaneously with the more common 47, XXYcases (Utah Department of Health, 1993).
Another possible variant is a mosaic individual which means that he possesses two or more different cell lines differing in the number of chromosomes (Robinson et. al., 1994). A mosaic Klinefelter male, which is much less common than the other types, would have a 46, XY/47, XXY
karyotype. Klinefelter syndrome in these individuals can be more or less severe, depending on which cell line is used for the symptomatic traits.
Exact diagnosis of Klinefelter Syndrome requires karyotyping of the patient to detect the numerical chromosome aberration 47, XXY or one of its variants. It involves examining the arrangement of chromosomes on the DNA from a blood, bone marrow, amniotic fluid, or placental tissue sample (Orbis Broadcast Group, 1998). Some Klinefelter boys are being diagnosed prenatally when karyotyping is done for the detection of Down syndrome and other major aneuploidies. But less than ten percent of the estimated number of affected fetuses were actually detected in a study done by Abramsky and Chapple. Other tests can be performed to confirm Klinefelter Syndrome if it is already suspected due to expressed symptoms. Blood tests which show high levels of LH
and FSH are a positive indication (Orbis Broadcast Group, 1998). The presence of Bar bodies from oral swabs also indicates a Klinefelter male, because they cannot be formed unless inactivation of an extra X-chromosome is occurs. One of the most accelerated diagnosis tools
also deals with X-inactivation. It is the detection of XIST gene expression in peripheral blood leukocytes. The XIST gene, which is the marker for the inactivation of extra X-chromosomes can be identified by PCR (Kleinheinz and Schulze, 1994).
The prognosis for Klinefelter patients is bright in some areas and unclear in others. To deal with the lack of secondary sexual features and other problems caused by low quantities of testosterone, there is testosterone therapy. Testosterone should be administered starting at eleven to twelve years of age, when puberty normally begins. The benefit is a more normal appearance including weight gain, increased muscle mass, increased hair distribution, acne, and less feminization
(Slywka, 1994). If the syndrome is diagnosed later in life, testosterone treatmentsshould still be helpful and effective and usually increase sex drive. These treatments are available in oral,
injectable, and patch therapy form. If gynecomastia is already prevalent, breast reduction surgery is a feasible option.
Treatment of language impairment caused by Klinefelter Syndrome is the same for non-Klinefelter-related speech disorders. It is vital that language therapy begins at a young age to be completely successful. With appropriate attention from a speech therapist, the effects of
these problems on learning can be reduced significantly, allowing only slightly displaced intelligence.
Unfortunately, the most severe symptom of Klinefelter Syndrome, infertility, has the had the bleakest outlook for a long time. Although the missing testosterone due to disfunction in the testes can
be artificially supplied, the changes in the testes that lead to infertility are not preventable (Orbis Broadcast Group). Generally, gonadotrophic hypogonadism and azoospermia are the specific conditions in the testes of Klinefelter males. Occasionally, severe oligozoospermia may be present but usually only in the mosaic karyotype (Tournaye et. al., 1996). Until recently, there was no hope
for infertile Klinefelter patients to have children. However, new studies have shown that in some cases, Klinefelter males can indeed become fathers.
The first question that had to be answered before further research could be done was whether or not infertile Klinefelter men produce any functional sperm at all. This question was answered in a study done by Cozzi et. al. in which meiosis in 47, XXY cells to form spermatozoa was confirmed. With the knowledge that viable spermatozoa may exist in these men, the next step was to try to access it.
In a study conducted by Tournaye et. al., the possibility of recovering testicular spermatozoa from 47, XXY patients for use in intracytoplasmic sperm injection (ICSI) was investigated. If spermatozoa can be recovered from Klinefelter's males with abnormal seminiferous tubules, ICSI allows their partners' oocytes to be impregnated and placed in the uterus for normal development. Hence,
the Klinefelter man's sexual incapacity is overcome. This is a common infertility treatment for couples with a normal 46, XY male. The feat in making it work in a 47, XXY male is the actual recovery of sperm. In four out of nine patients, spermatozoa were recovered from testicular tissue. Although the results proved this to be a fairly successful infertility treatment, the authors consider the procedure experimental with concerns for the chromosomal normality in the embryos generated by ICSI. This complex treatment involves multiple testicular biopsies and preimplantation diagnosis of embryos, making it much more complicated than it sounds.
Primplantation diagnosis for the specific purpose of X and Y normality in embryos from Klinefelter patients obtained by ICSI was the focus of a study done by Staessen et. al. Five embryos were biopsied and diagnosed by fluorescent in-situ hybridization. Four were found to have normal sex chromosome patterns, and one resulted in a successful pregnancy. The implication of using primplantation diagnosis for ICSI of sperm recovered from Klinefelter patients is the procreation of
healthy children with Klinefelter fathers. This is an enormous step in refining infertility treatment of Klinefelter males. Although it is still experimental, it has beenproven to work and exists as an option
for couples capable of enduring the emotional, physical, and financial hardships of the procedure.
Works Cited
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study of 543 sperm karyotypes from an XY/XXY mosaic patient. Human Genetics. 93: 32-4.
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