Information

Can men with Klinefelter syndrome produce chromosomally normal sperm?


Individuals with Klinefelter syndrome are XXY. Even though sperm counts are low some individuals can generate enough to be used in IVF and have offspring.

Does this mean that when sperm are formed, the process works correctly to separate all 3 of them and only sperm with a single sex chromosome are formed?

(Excluding same genetic issues happening again of course)


Klinefelter syndrome

Between 1 in 500 and 1 in 1000 males have Klinefelter syndrome [1]. Variants of Klinefelter syndrome occur more infrequently approximately 1 in 50,000 or fewer newborns has a variant of Klinefelter syndrome[2].

Most men are diagnosed as adults in the context of male infertility. Only 10% of males with Klinefelter syndrome are diagnosed before age 14 years. Klinefelter syndrome is underdiagnosed because the condition is often not identified in men with mild signs and symptoms. Additionally, features can vary and overlap with other conditions[1].

Klinefelter syndrome is one of the leading causes of male infertility. Approximately 3% of all infertile men have Klinefelter syndrome[1] and 14% of non-obstructive azoospermic men have Klinefelter syndrome[3].

Klinefelter syndrome is a chromosomal condition that affects male physical and cognitive development. The syndrome is the result of one additional X chromosome, or a 47,XXY karyotype. The extra X chromosome interferes with male sexual development, often preventing the testes from functioning normally and reducing the levels of testosterone.

Some individuals have a variant of Klinefelter syndrome- meaning they have more than one additional X chromosome, such as a 48,XXXY or 49,XXXXY karyotype. These individuals may experience more severe signs and symptoms.

Klinefelter syndrome and its variants are not inherited. Klinefelter syndrome occurse due to a random event when the reproductive cells (eggs and sperm) are forming in the parent. The random event is called nondisjunction and the resulting reproductive cell has an abnormal number of chromosomes. Nondisjunction is often associated with increased maternal age[1].

The mosaic forms of Klinefelter syndrome, like 46,XY/47,XXY are also not inherited. Mosaic Klinefelter syndrome results from a random event in cell division early in fetal development. As a result- there are two cell lines within the body. Individuals with mosaic Klinefelter may have less severe signs and symptoms.

The signs and symptoms of individuals with Klinefelter syndrome (47,XXY) and its variants tend to vary among affected individuals[2]. The following are characteristic of Klinefelter syndrome:

  • microorchidism (small testes)
  • cryptorchidism (undescended testes)
  • hyopspadius (the opening of the urethra is on the underside of the penis)
  • micropenis
  • tall stature
  • learning disabilities
  • delayed speech and language development

There is also an increased risk for breast cancer and systemic lupus erythematosus.

Individuals with variants of Klinefelter (more than one extra chromosome, like 48,XXXY and 49,XXXXY) may have intellectual disabilities, distinctive facial features, skeletal abnormalities, poor coordination, and severe speech problems. As the number of extra sex chromosomes increases, so does the risk of developing these more severe health problems[2].

Individuals with Klinefelter syndrome typically have microorchidism (small testes) and do not produce adequate levels of testosterone. Testosterone directs male sexual development before birth and during puberty. A shortage of testosterone can lead to delayed or incomplete puberty, gynecomastia, reduced facial and body hair, and infertility[2].

Infertilty is typically due to severe spermatogenesis impairment responsible for azoospermia in

90% of men with Klinefelter syndrome (47,XXY) and

75% of men with mosaic Klinefelter syndrome[4].

Fertility preservation may be best proposed to adolescent Klinefelter patients, just after the onset of puberty, when it is possible to collect a semen sample and when the patient is able to consider alternative options to achieve fatherhood and also accept the failure of spermatozoa or immature germ cell retrieval[5]. Additionally, successful sperm retrieval may decrease with age and after testosterone therapy, further warranting fertility preservation during adolesence[3]. The following are methods for preserving fertility in those with Klinefelter syndrome:

Testicular Sperm Extraction (TESE)

TESE invovles extracting viable sperm cells from testicular tissue after a testicular biopsy. Pening et al. (2014) reported successful recovery in 20% of study participants with Klinefelter syndrome who underwent TESE[7]. TESE can be combined with itracytoplasmic sperm injection (ICSI) and in vitro fertilization (IVF) it offers the opportunity for Klinefelter patients with azoospermia to father children with their own spermatozoa. However, successful retrieval decreases with age and after testosterone therapy[3], therefore it is important to discuss the option of TESE with adolescents or quickly after diagnosis of Klinefelter syndrome in adult men. Normal fertilization, embryo development, pregnancies, and births have been achieved after TESE and ICSI for men with Klinefelter syndrome[6].

Spermatogonial Stem Cell (SSC) Banking

Germ cell depletion begins at the onset of puberty and leads to infertility, therefore banking SSCs, also called immature germ cells, has been proposed as a strategy to preserve fertility in adolescents with Klinefelters syndrome. For optimal preservation of SSCs, spermatogonia should be retrieved by testicular biopsy preferably before the testis hyalinization occurs[8].

For those without azoospermia or before undergoing testosterone replacement therapy, sperm cells may be collected after ejaculation and frozen for future use. This may be a better option for those men with mosaic Klinefelter syndrome, as most men with Klinefelter have azoospermia. Read more information about sperm banking.

Couples considering having biological children should be offered the option of preimplantation genetic diagnosis (PGD) to ensure the embryo selected in karyotypically normal[3].

[1]Bojesen, A., Juul, S., & Gravholt, C. (2003). Prenatal and postnatal prevalence of Klinefelter syndrome: a national registry study. J Clin Endocrinol Metab, 88, 622-626.

[2]Klinefelter syndrome. (2013). U.S. National Library of Medicine.http://ghr.nlm.nih.gov/condition/klinefelter-syndrome Retrieved May 20, 2014

[3]Krausz, C., & Chianese, C. (2014). Genetic testing and counseling for male infertility. Curr Opin Endocrinol Diabetes Obes, 21(3), 244-250.

[4]Mau-Holzmann, U. (2005). Somatic chromosomal abnormalities in infertile men and women. Cytogenet Genome Res, 111, 317-336.

[5]Rives, N., Milazzo, J., Perdrix, A., Castanet, M., Joly-Helas, G., Sibert, L., . . . Mace, B. (2013). The feasibility of fertility preservation in adolescents with Klinefelter syndrome. Hum. Reprod., 28(6), 1468-1479.

[6]Fullerton, G., Hamilton, M., & Maheshwari, A. (2010). Should non-mosaic Klinefelter syndrome men be labeled as infertile in 2009? Hum Reprod, 25(588-597).

[7]Pening, D., Delbaere, A., & Devreker, F. (2014). Predictive factors of sperm recovery after testicular biopsy among non-obstructive azoospermic patients. Obstet. Gynecol., 123(Suppl 1), 189S-190S.

[8]van Saen, D., Gies, I., & De Schepper, J. (2012). Can pubertal boys with klinefelter syndrome benefit from spermatogonial stem cell banking? Hum Reprod, 27, 323-330.

About the Author

Allison Goetsch, MS, CGC is a pediatric genetic counselor at Ann and Robert H. Lurie Children's Hospital of Chicago and a member of the Oncofertility Consortium administrative core team. She completed her graduate thesis with Dr. Teresa K. Woodruff researching oncofertility and hereditary breast and ovarian cancer (HBOC) syndrome. Allison's primary goals are to increase fertility preservation awareness and education for both health care providers and patients regarding malignant and non-malignant diseases (and/or treatments) which threaten fertility.


Klinefelter syndrome is a condition that occurs in men as a result of an extra X chromosome. The most common symptom is infertility.

Humans have 46 chromosomes, which contain all of a person's genes and DNA. Two of these chromosomes, the sex chromosomes, determine a person's gender. Both of the sex chromosomes in females are called X chromosomes. (This is written as XX.) Males have an X and a Y chromosome (written as XY). The two sex chromosomes help a person develop fertility and the sexual characteristics of their gender.

Most often, Klinefelter syndrome is the result of one extra X (written as XXY). Occasionally, variations of the XXY chromosome count may occur, the most common being the XY/XXY mosaic. In this variation, some of the cells in the male's body have an additional X chromosome, and the rest have the normal XY chromosome count. 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.

Klinefelter syndrome is found in about 1 out of every 500-1,000 newborn males. The additional sex chromosome results from a random error during the formation of the egg or sperm. About half of the time the error occurs in the formation of sperm, while the remainder are due to errors in egg development. Women who have pregnancies after age 35 have a slightly increased chance of having a boy with this syndrome.

Klinefelter syndrome is a condition that occurs in men as a result of an extra X chromosome. The most common symptom is infertility.

Humans have 46 chromosomes, which contain all of a person's genes and DNA. Two of these chromosomes, the sex chromosomes, determine a person's gender. Both of the sex chromosomes in females are called X chromosomes. (This is written as XX.) Males have an X and a Y chromosome (written as XY). The two sex chromosomes help a person develop fertility and the sexual characteristics of their gender.

Most often, Klinefelter syndrome is the result of one extra X (written as XXY). Occasionally, variations of the XXY chromosome count may occur, the most common being the XY/XXY mosaic. In this variation, some of the cells in the male's body have an additional X chromosome, and the rest have the normal XY chromosome count. 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.

Klinefelter syndrome is found in about 1 out of every 500-1,000 newborn males. The additional sex chromosome results from a random error during the formation of the egg or sperm. About half of the time the error occurs in the formation of sperm, while the remainder are due to errors in egg development. Women who have pregnancies after age 35 have a slightly increased chance of having a boy with this syndrome.


Social and Behavioral Symptoms

Many of the social and behavioral symptoms in KS may result from the language and learning difficulties. For instance, boys with KS who have language difficulties might hold back socially and could use help building social relationships.

Boys with KS, compared to typically developing boys, tend to be:

  • Quieter
  • Less assertive or self-confident
  • More anxious or restless
  • Less physically active
  • More helpful and eager to please
  • More obedient or more ready to follow directions

In the teenage years, boys with KS may feel their differences more strongly. As a result, these teen boys are at higher risk of depression, substance abuse, and behavioral disorders. Some teens might withdraw, feel sad, or act out their frustration and anger.

As adults, most men with KS have lives similar to those of men without KS. They successfully complete high school, college, and other levels of education. They have successful and meaningful careers and professions. They have friends and families.

Contrary to research findings published several decades ago, males with KS are no more likely to have serious psychiatric disorders or to get into trouble with the law. 10


Klinefelter syndrome

Klinefelter syndrome is a genetic disorder that affects males. Klinefelter syndrome occurs when a boy is born with one or more extra X chromosomes. Most males have one Y and one X chromosome. Having extra X chromosomes can cause a male to have some physical traits unusual for males.

It is a chromosomal condition that affects male sexual development. Males with this condition typically have small testes that do not produce enough testosterone, which is the hormone that directs male sexual development before birth and during puberty. A shortage of testosterone during puberty can lead to breast enlargement (gynecomastia), reduced facial and body hair, and an inability to father children (infertility).

Other names for Klinefelter syndrome:

The X chromosome carries genes that play roles in many body systems, including testis function, brain development, and growth.The addition of more than one extra X or Y chromosome to a male karyotype results in variable physical and cognitive abnormalities. In general, the extent of phenotypic abnormalities, including mental retardation, is directly related to the number of supernumerary X chromosomes. As the number of X chromosomes increases, somatic and cognitive development are more likely to be affected.

Klinefelter’s syndrome is caused by an extra X chromosome and affects only males. An infant with Kleinnfelter’s Syndrome appears normal at birth, but the defect usually becomes apparent in puberty when secondary sexual characteristics fail to develop, and testicular changes occur that eventually result in infertility in the majority of those affected.

But it can also occur when the genetic material in the sperm splits unevenly.

  • Small penis
  • Small firm testicles
  • Diminished pubic
  • Axillary
  • Reduced facial and body hair.
  • Infertility
  • Sexual dysfunction
  • Enlarged breast tissue
  • Tall stature
  • Abnormal body proportions (long legs, short trunk),
  • Learning disabilities,
  • Personality impairment,
  • A single crease in the palm.

What are the genetic changes related to Klinefelter syndrome?

Klinefelter syndrome is a condition related to the X chromosome and Y chromosome (the sex chromosomes). People typically have two sex chromosomes in each cell: females have two X chromosomes (46,XX), and males have one X and one Y chromosome (46,XY). Most often, Klinefelter syndrome results from the presence of a single extra copy of the X chromosome in each of a male’s cells (47,XXY). Extra copies of genes on the X chromosome interfere with male sexual development, preventing the testes from functioning normally and reducing the levels of testosterone.Some males with Klinefelter syndrome have the extra X chromosome in only some of their cells in these individuals, the condition is described as mosaic Klinefelter syndrome.

Treatment for Klinefelter syndrome :

  • Androgen therapy
  • Speech and behavioral therapy
  • Treatment for infertility
  • Physical and occupational therapy

Other treatment for Klinefelter syndrome may include:

Testosterone replacement therapy: Males with Klinefelter syndrome don’t produce enough of the male hormone testosterone, and this can have lifelong effects. Starting at the time of the usual onset of puberty, testosterone replacement can help treat or prevent a number of problems. Testosterone may be given as injections or with a gel or patch on the skin. Testosterone replacement therapy allows a boy to undergo the body changes that normally occur at puberty, such as developing a deeper voice, growing facial and body hair, and increasing muscle mass and penis size. Testosterone therapy also can help reduce growth of breast tissue, improve bone density and reduce the risk of fractures. It will not result in testicle enlargement or improve infertility.

Breast tissue removal: In males who develop enlarged breasts (gynecomastia), excess breast tissue can be removed by a plastic surgeon, leaving a normal-looking chest.

Speech and physical therapy: These treatments can help boys with Klinefelter syndrome overcome problems with speech, language and muscle weakness.

Educational support: Some boys with Klinefelter syndrome have trouble learning and can benefit from extra assistance. Talk to your child’s teacher, school counselor or school nurse about what kind of support might help.

Fertility treatment: Most men with Klinefelter syndrome are unable to father children, because no sperm are produced in the testicles. Some men with Klinefelter syndrome may have some minimal sperm production. One option that may benefit these men is a procedure called intra-cytoplasmic sperm injection (ICSI), in which sperm is removed from the testicle with a biopsy needle and injected directly into the egg. Other alternatives for having children include adoption and artificial insemination with donor sperm.

Psychological counseling: Having Klinefelter syndrome can be a challenge, especially during puberty and young adulthood. For men with the condition, coping with infertility can be difficult. A family therapist, counselor or psychologist can help you work through emotional issues.

Medical Complications of Klinefelter Syndrome:

Some of the medical complications from Klinefelter Syndrome are:

  • An increased risk of developing breast cancer,
  • Pulmonary disease,
  • Varicose veins,
  • Osteoporosis,
  • Aicardi syndrome, and
  • Lung disease.

Can Klinefelter syndrome be inherited?

This condition is not inherited it usually occurs as a random event during the formation of reproductive cells (eggs and sperm). An error in cell division called non-disjunction results in a reproductive cell with an abnormal number of chromosomes.


Understanding Klinefelter syndrome: a guide for XXY males and their families.

In 1942, Dr. Harry Klinefelter and his coworkers at the Massachusetts General Hospital in Boston published a report about nine men who had enlarged breasts, sparse facial and body hair, small testes, and an inability to produce sperm.

By the late 1950s, researchers discovered that men with Klinefelter syndrome, as this group of symptoms came to be called, had an extra sex chromosome, XXY instead of the usual male arrangement, XY. (For a more complete explanation of the role this extra chromosome plays, see the accompanying section, "Chromosomes and Klinefelter syndrome.")

In the early 1970s, researchers around the world sought to identify males having the extra chromosome by screening large numbers of newborn babies. One of the largest of these studies, sponsored by the National Institute of Child Health and Human Development (NICHD), checked the chromosomes of more than 40,000 infants.

Based on these studies, the XXY chromosome arrangement appears to be one of the most common genetic abnormalities known, occurring as frequently as 1 in 500 to 1 in 1,000 male births. Although the syndrome's cause, an extra sex chromosome, is widespread, the syndrome itself-the set of symptoms and characteristics that may result from having the extra chromosome-is uncommon. Many men live out their lives without ever even suspecting that they have an additional chromosome. "I never refer to newborn babies as having Klinefelter's, because they don't have a syndrome," said Arthur Robinson, M.D., a pediatrician at the University of Colorado Medical School in Denver and the director of the NICHD-sponsored study of XXY males. "Presumably, some of them will grow up to develop the syndrome Dr. Klinefelter described, but a lot of them won't."

For this reason, the term "Klinefelter syndrome" has fallen out of favor with medical researchers. Most prefer to describe men and boys having the extra chromosome as "XXY males."

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. For the most part, these symptoms are treatable. Surgery, when necessary, can reduce breast size. Regular injections of the male hormone testosterone, beginning at puberty, can promote strength and facial hair growth-as well as bring about a more muscular body type.

A far more serious symptom, however, is one that is not always readily apparent. Although they are not mentally retarded, most XXY males 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 begun in early childhood. Sections that follow describe possible strategies for meeting the special educational needs of many XXY males.

CHROMOSOMES AND KLINEFELTER SYNDROME

Chromosomes, the spaghetti-like strands of hereditary material found in each cell of the body, determine such characteristics as the color of our eyes and hair, our height, and whether we are male or female.

Women usually inherit two X chromosomes--one from each parent. Men tend to inherit an X chromosome from their mothers, and a Y chromosome from their fathers. Most males with the syndrome Dr. Klinefelter described, however, have an additional X chromosome--a total of two X chromosomes and one Y chromosome.

No one knows what puts a couple at risk for conceiving an XXY child. Advanced maternal age increases the risk for the XXY chromosome count, but only slightly. Furthermore, recent studies conducted by NICHD grantee Terry Hassold, a geneticist at Case Western Reserve University in Cleveland, OH, show that half the time, the extra chromosome comes from the father.

Dr. Hassold explained that cells destined to become sperm or eggs undergo a process known as meiosis. In this process, the 46 chromosomes in the cell separate, ultimately producing two new cells having 23 chromosomes each. Before meiosis is completed, however, chromosomes pair with their corresponding chromosomes and exchange bits of genetic material. In women, X chromosomes pair in men, the X and Y chromosome pair. After the exchange, the chromosomes separate, and meiosis continues.

In some cases, the Xs or the X chromosome and Y chromosome 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 Y- bearing sperm fertilizes an egg having two X chromosomes, an XXY male is conceived.

Because they often don't appear any different from anyone else, many XXY males probably never learn of their extra chromosome. However, if they are to be diagnosed, chances are greatest at one of the following times in life: before or shortly after birth, early childhood, adolescence, and in adulthood (as a result of testing for infertility).

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, 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.

"If I were going to say something to parents who have had a prenatal diagnosis, it would be 'You are so lucky that you know,'" said Melissa, the mother of one XXY boy. "Because there are parents who don't know that their sons have this problem. And they will never be able to help them lead a normal life. But you can."

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.

A few XXY males are diagnosed at adolescence, when excessive breast development forces them to seek medical attention. Like some chromosomally normal males, many XXY males undergo slight breast enlargement at puberty. Of these, only about a third-- 10 percent of XXY males in all-will develop breasts large enough to embarrass them.

The final chance for diagnosis is at adulthood, as a result of testing for infertility. At this time, an examining physician may note the undersized testes characteristic of an XXY male. In addition to infertility tests, the physician may order tests to detect increased levels of hormones known as gonadotropins, common in XXY males.

A karyotype is used to confirm the diagnosis. In this procedure, a small blood sample is drawn. White blood cells are then separated from the sample, mixed with tissue culture medium, incubated, and checked for chromosomal abnormalities, such as an extra X chromosome.

WHAT TO TELL FAMILIES, FRIENDS, AND XXY BOYS

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. Fortunately, however, there are some guidelines that new parents can take into account when making their decisions.

One school of thought holds that the best course is to go on slowly, waiting at least 1 year before telling anyone-- grandparents included-about the child's extra chromosome. Many people are frightened by the diagnosis, and their fears will color their perceptions of the child. For example, some people may confuse the term Ktinefelter syndrome with Down syndrome, a condition resulting in mild to moderate mental retardation. Others may prefer to reveal the diagnosis early. Some parents have found that grandparents, aunts, uncles-and even extended family members-are more supportive when given accurate information. 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 roughly the age of 12, depending on the child'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 make 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, late in the teen years.

Conversely, other experts believe that holding back 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 this reason, 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.

According to Dr. Robinson, the director of the NICHD-funded study, 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, and may have similar delays in learning to speak.

In some, the language delays may be more 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 in learning to 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.

"It's one of the conflicts they have," said Melissa, the mother of an XXY boy. "My son can understand the conversations of other 10-year olds. But his inability to use the language the way other 10-year olds use it makes him stand out."

In addition to academic help, 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.

Throughout childhood-perhaps, even, for the rest of their lives- XXY boys 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. Researchers also describe them as cooperative and eager to please.

DETECTING LANGUAGE PROBLEMS 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. (The American Speech, Language and Hearing Association. listed in the reference section, distributes a free pamphlet on the stages of language development during the first 5 years of life.)

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.

GUIDELINES FOR DETECTING 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 a child is not communicating effectively with single words by 18 to 24 months, then parents should seek a consultation with a speech and language pathologist.

THE XXY BOY IN THE CLASSROOM

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, they 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.

According to Dr. Robinson, XXY boys do best in small, uncrowded classrooms where teachers can give them a lot of individual attention. He suggests that parents who can meet the expense 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. For in- depth information on Public Law 94-142, parents may contact the National Information Center for Children and Youth with Disabilities (NICHCY), listed in the Resources section.

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 parents groups may be able to tell parents where they can enroll in such a course.

For information on learning disabilities, parents can contact the Learning Disabilities Association of America and the Orton Dyslexia Society, both listed in the reference section.

Services for infants, toddlers and preschoolers

The chances for reducing 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. To learn the agencies to contact in their area, parents may call the Federation for Children with Special Needs (listed in the Resources section). The NICHCY (also listed in the Resources section) distributes the brochure "A Parent's Guide to Accessing Programs for Infants, Toddlers, and Preschoolers with Handicaps."

XXY males 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 will 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-engaging them in conversation through a series of questions. The same technique can be used to get 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 get 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 oneself. For instance, if a younger child indicated that he wanted 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 asked "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. First, teachers can reduce distraction 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.

As mentioned above, 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. Again, the parent or teacher should gently shift the child's attention, by saying something like "Drawing time is over. Let's put away the crayons and take out the math book."

-Adapted from John Graham et al., "Oral and Written Language Abilities of XXY Boys: Implications for Anticipatory Guidance." Pediatrics, Vol. 81 (6), June 1988.

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. Furthermore, 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. More information about testosterone and XXY males can be found in the section titled "Testosterone Treatment." 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. "They're usually tall, good-looking kids, but they tend to be awkward," Dr. Robinson said of the XXY teenagers he has met through his study. "They don't necessarily make good football players or good basketball players."

Lack of strength and agility, combined with a history of learning disabilities, may damage self-esteem. Unsympathetic peers, too, sometimes may make matters worse, through teasing or ridicule. "Lots of kids have a tough time during adolescence," Dr. Robinson said. "But a higher proportion of XXY boys have a tough time. High school is very competitive, and these kids are not very good competitors, in general."

Dr. Robinson again stressed, however, that while XXY males share many characteristics, they cannot be pigeonholed into rigid categories. Several of his patients have played football, and one, in particular, is an excellent tennis player.

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 scholastic difficulties as laziness. Lack of athletic prowess and the inability to use language properly in social settings may have helped to isolate them from their peers. Some may react by sliding quietly into depression and withdraw from contact with other people. Others may find acceptance in a dangerous crowd.

For these reasons, XXY males diagnosed as teenagers may need psychological counseling as well as help in overcoming their learning disabilities. Help with learning disabilities is available through public school systems for XXY males high-school age and under. Referrals to qualified mental health specialists may be obtained from family physicians.

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 will increase strength and muscle size, and promote the growth of facial and body hair.

In addition to these physical changes, testosterone injections often bring on 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 changes in moods.

What is not clear is whether these psychological changes are a direct result of 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 changes in mood are typical of depressed people.

Other benefits of testosterone treatment may include decreased need for sleep, an enhanced ability to concentrate, and improved relations with others. But to obtain these benefits an XXY male must decide, on his own, that he is ready to stick 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 may respond to testosterone treatment in different ways. Although the majority of XXY males ultimately will benefit from testosterone, a few will 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 specialist in hormonal interactions) who has experience treating XXY males.

Side effects of the 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.

In addition, testosterone injections may result in a condition known as benign prostatic hyperplasia (BPH). This condition is common in chromosomally normal males as well, 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. The prostate is a small gland about the size of a walnut, which helps to manufacture semen. The gland is located just beneath the bladder and surrounds the urethra, the tube through which urine passes out of the body.

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. BPH can often be detected early by a rectal exam. If the prostate greatly interferes with the flow of urine, excess prostate tissue can be trimmed away by a surgical instrument that is inserted in the penis, through the urethra.

Occasionally, variations of the XXY chromosome count may occur, the most common being the XY/XXY mosaic. In this variation, some of the cells in the male's body have an additional X chromosome, and the rest have the normal XY chromosome count. 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. A few instances of males having two or even three additional X chromosomes have also been reported in the medical literature. In these individuals, the classic features of Klinefelter syndrome may be exaggerated, with low I.Q. or moderate to severe mental retardation also occurring.

In rare instances, an individual may possess both an additional X and an additional Y chromosome. The medical literature describes XXYY males as having slight to moderate mental retardation. They may sometimes be aggressive or even violent. Although they may have a rounded body type and decreased sex drive, experts disagree whether testosterone injections are appropriate for all of them.

One group of researchers reported that after receiving testosterone injections, an XXYY male stopped having violent sexual fantasies and ceased his assaults on teenaged girls. In contrast, Dr. Robinson found that testosterone injections seemed to make an XXYY boy he had been treating more aggressive. Scientists admit, however, that because these cases are so rare, not much is known about them. Most of the XXYY males who have been studied were referred to treatment because they were violent and got into trouble with the law. It is not known whether XXYY males are inherently aggressive by nature, or whether only a few extreme individuals come to the attention of researchers precisely because they are aggressive.

The parents of XXY boys are sometimes concerned that their sons may grow up to be homosexual. This concern is unfounded, however, as there is no evidence that XXY males are any more inclined toward homosexuality than are other men.

In fact, 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've 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.

The vast majority of XXY males do not produce enough sperm to allow them to become fathers. If these men and their wives wish to become parents, they should seek counseling from their family physician regarding adoption and infertility.

However, 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.

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 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. The free booklet Breast Exams: What You Should Know is available from the National Cancer Institute, listed in the Resources section. The last page of the booklet is a pullout chart listing the instructions for breast self examination. Although the booklet was written primarily for women, the breast self examination technique also can be used by XXY males. XXY males may also wish to consult their physicians about the need for more thorough breast examinations by medical professionals.

In addition, 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.

Unfortunately, comparatively little is known about XXY adults. Studies in the United States 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. At this time, researchers simply do not know what kind of adults they will become. "Some of them have really struggled through adolescence," said Dr. Bruce Bender, the psychologist for the NICHD-sponsored study of XXY males. "But we don't know whether they'll have serious problems in adulthood, or, like many troubled teenagers, overcome their problems and lead productive lives."

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 represent a particular extreme.

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, that they were more productive on the job, and that 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.

The Orton Dyslexia Society and the Learning Disabilities Association of America, listed in the Resources section, can provide information on overcoming a reading disability.

Distributes a pamphlet parents may consult to determine if their children's communication abilities are developing at a normal rate.

The Federation for Children

95 Berkely Street, Suite 104

Maintains a listing of local and state agencies providing special educational services for infants, toddlers, and preschoolers under Public Law 99-457

Provides information on dyslexia and other learning disabilities. Has local chapters throughout the country.

Support group for XXY males as weft as males with other sex chromosome disorders. Operated by "Melissa," mother of a 12-year-old XXY boy. Provides literature on XXY males and other chromosome disorders, periodic newsletter.

The National Cancer Institute

Offers the free booklet Breast Exams: What You Should Know. The last page of the booklet is a pull-out chart listing the instructions for breast self examination. Although the booklet was written primarily for women, the breast self examination technique also can be used by XXY males.

Center for Children and Youth

Distributes information on Public Law 94-142, the Individuals with Disabilities Education Act.

The Orton Dyslexia Society

Chester Building, Suite 382

Provides information on dyslexia. Has local chapters throughout the country.


4 Discussion

4.1 Genetic risk of the intracytoplasmic sperm injection treatment for patients with Klinefelter syndrome

The present study showed that 45 babies were successfully delivered by using oocyte penetration by sperm or spermatid from patients with KS from January 2000 to December 2013 at the institute and, among them, there was neither a case of chromosomal abnormality nor any case of physical or cognitive abnormality. The miscarriage rate (37.3%) in the treatment of patients with KS by using sperm and spermatid was not significantly higher, when compared with patients who do not have KS (20.1% of 134). 30 The results indicate the possibility that the genetic risk of the embryos that are produced in the treatment of patients with KS is not as high as previously believed.

This clinical result is consistent with the cytogenetic data of the FISH and chromosomal analysis in the gametes from patients with KS. In the 25 patients with KS who were examined, no sex chromosome abnormality was found in 952 ST cells and 100 sperm (Table 2). The mechanism to produce normal gametes in the testis of patients with KS is considered to be as follows. In patient no. 2, all the SG and Pr-SCs that were analyzed were XY in their sex chromosome constitution. Therefore, there is no doubt that STs with X or Y chromosomes could be derived from the meiosis of sex chromosomally normal germ cells. In the remaining four patients with KS with testicular mosaicism of XY and XXY SG, it is difficult to determine which of the XY or XXY cells were the source of the STs. However, in all of their Pr-SCs that were analyzed, the sex chromosome constitution was XY, and accordingly, all the ST cells might have been produced from XY SG, suggesting the possibility that XXY SG cannot enter meiosis. Another study also has reported that there was no XXY pachytene gamete and no increase of XY STs or XY sperm in three testicular 46 XY/47XXY mosaic patients with KS, reaching the conclusion that 46 XY cells can undergo meiosis. 12 There is another possibility that the resultant abnormal daughter cells of XXY SG can become degenerative or apoptotic, 37 because in this study, only the spermatogenic cells that were alive with the intact plasma membrane and smooth round shape were selectively examined. This possibility seems to be a reason for an inconsistency of the present data with those of previous cytogenetic studies in patients with KS. Many previous FISH studies have reported that not only the sex chromosome abnormality rate, but also the rate of autosomal aneuploidies, 24 is higher in sperm from patients with KS than from infertile patients without KS. 24-29 In those studies, the testicular cell suspension was directly smeared onto a glass slide, treated with dithiothreitol, and hybridized with FISH probes. As after the successive treatment, the artificially swollen sperm heads were not allowed to be evaluated for their morphology, a tail was used to identify the sperm. Therefore, it cannot be denied that aberrant sperm heads, which are not appropriate for ICSI treatment, must have been analyzed along with normal sperm heads in the previous FISH studies. It is a clear fact that the risks of disomy and diploidy are higher in sperm with aberrant heads. 38, 39 In addition, this assumption is supported by the high frequency of XY sperm that has been found in the control donor sperm that are used in FISH studies because the rates of XY sperm that were obtained were 20-100-fold higher than the rate (0.018%) that was reported by a study that used a chromosome assay of 15 864 ejaculated donor sperm (n=51) that penetrated hamster oocytes. 40 The authors understand that the reason for the distinct results between the current and the previous FISH studies cannot be revealed without a comparative study among the different sperm selection procedures. However, it can be concluded that, instead of using a testicular cell suspension, the authors’ cytogenetic studies with spermatogenic cells that were morphologically evaluated and selected are more suitable for the exact estimation of the genetic risk in the ICSI treatment of patients with KS. In constrast, a study reported an increase of sex chromosome aneuploidy in array comparative genomic hybridization with the trophoblasts that had been biopsied from embryos obtained by the ICSI treatment of men with oligozoospermia, 41 suggesting the risk of the use of suboptimal sperm. Although it is not clear whether patients with KS are included in their data, the result seems to disagree with the present data. However, their data include some points that are hard to understand. First, the total aneuploidy rates did not differ among the embryos from IVF and ICSI with normal and suboptimal sperm groups. Second, in the embryos of the suboptimal sperm group, aneuploidy increased in specific autosomes in addition to the sex chromosomes. These incompatible phenomena seem to be explained by the possibility that patients with genetic backgrounds causing aneuploidy of a specific chromosome(s) are contained in the oligozoospermia group. Therefore, their result might not necessarily be applicable to patients with KS, although close attention has to be paid to the genetic risk of ICSI treatment of patients with KS.

4.2 Contribution of the XX oocyte in the production of Klinefelter syndrome

When the current study found that no XY aneuploidy could be observed in the gametes of patients with KS in the authors’ cytogenetic analysis, it was hypothesized that the XY sperm did not contribute to the production of KS as much as the XX oocytes. In this X-chromosome STR analysis, the patients with maternal origin X chromosomes were comparably frequent (63.6%), suggesting that the contribution of the XX oocyte to the production of XXY embryos might be greater than by the XY sperm, although the sample number that was applied for the X-chromosomal STR DNA profiling is not large enough. Some studies have previously attempted to determine the origin of the extra X chromosome in patients with KS with X-chromosome restriction site polymorphism. 42-44 The maternal contribution to the production of KS was slightly greater in two studies (59% vs 41%) and was slightly lower in one study (42.8% vs 57.1%). In those studies, however, there were cases in which the X-chromosome origin was determined by the appearance or disappearance of a single band in a single allele, which might have resulted from mutation. In the X-chromosome STR analysis, the 12 X-chromosomal markers are clustered into four linkage groups, which consist of three alleles, and thus each set of three markers is handled as a haplotype for genotyping to avoid misjudgment. The authors could find no previous study that applied X-chromosome STR with PCR to patients with KS. One study reported that the extra X chromosome is the result of meiotic non-disjunction 45 or possibly, as recently described, of the premature separation of sister chromatids, both paternally or maternally, because of an increased maternal age. 1, 46 As the X-chromosome origin can affect the potency of spermatogenesis in patients with KS, the authors will collect further data by using this method.


Can men with Klinefelter syndrome produce chromosomally normal sperm? - Biology

19. Chromosomes and Cell Division

In the previous few chapters, we considered reproduction and development. In this chapter, we examine the role of two types of cell division, mitosis and meiosis, in the human life cycle. We consider the physical basis of heredity—the chromosomes—and we consider how the chromosomes are parceled out during mitosis and meiosis. We finish the chapter by examining why it is important for each cell to have the correct number of chromosomes.

Two Types of Cell Division

We begin life as a single cell called a zygote, formed by the union of an egg and a sperm. By adulthood, our bodies consist of trillions of cells. What happened in the intervening years? How did we go from a single cell to the multitude of cells that make up the tissues of a fully functional adult? The answer is cell division, which happened over and over again as we grew. Even in adults, many cells continue to divide for growth and repair of body tissues. With very few exceptions, each of those cells carries the same genetic information as its ancestors. The type of nuclear division that results in identical body cells is called mitosis.

In Chapter 17 you learned that males and females produce specialized reproductive cells called gametes (eggs or sperm). You'll recall that meiosis is a special type of nuclear division that gives rise to gametes. In females, meiosis occurs in the ovaries and produces eggs. In males, meiosis occurs in the testes and produces sperm. Meiosis is important because through it the gametes end up with half the amount of genetic information (half the number of chromosomes) in the original cell. When the nuclei of an egg and sperm unite (fertilization), the chromosome number is restored to that of the original cell. As a result, the number of chromosomes in body cells remains constant from one generation to the next.

· Down syndrome, which results from an error in cell division, is the most frequent inherited cause of mild to moderate retardation.

The roles of mitosis (which produces new body cells) and meiosis (which forms gametes) are summarized in the diagram of the human life cycle in Figure 19.1. You will learn more about both mitosis and meiosis later in this chapter.

FIGURE 19.1. The human life cycle

A chromosome is a tightly coiled combination of a DNA molecule (which contains genetic information for the organism) and specialized proteins called histones. Chromosomes are found in the cell nucleus. The information contained in the DNA molecules in chromosomes directs the development and maintenance of the body. The histones combined with the DNA are for support and control of gene activity. A gene is a specific segment of the DNA that directs the synthesis of a protein, which in turn plays a structural or functional role within the cell. By coding for a specific protein, a gene determines the expression of a particular characteristic, or trait. Each chromosome in a human cell contains a specific assortment of genes. Like beads on a string, genes are arranged in a fixed sequence along the length of specific chromosomes.

In the human body, somatic cells—that is, all cells except for eggs or sperm—have 46 chromosomes. Those 46 chromosomes are actually 23 pairs of chromosomes. One member of each pair came from the mother's egg, and another member of each pair came from the father's sperm. Thus, each cell contains 23 homologous chromosome pairs, a pair being two chromosomes (one from the mother and one from the father) with genes for the same traits. Homologous pairs are called homologues for short. Any cell with two of each kind of chromosome is described as being diploid (annotated as 2n, with n representing the number of each kind of chromosome). In diploid cells, then, genes also occur in pairs. The members of each gene pair are located at the same position on homologous chromosomes.

One of the 23 pairs of chromosomes consists of the sex chromosomes that determine whether a person is male or female. There are two types of sex chromosomes, X and Y. A person who has two X chromosomes is described as XX and is genetically female a person who has an X and a Y chromosome is described as XY and is genetically male. The other 22 pairs of chromosomes are called the autosomes. The autosomes determine the expression of most of a person's inherited characteristics.

In mitosis, one nucleus divides into two daughter nuclei containing the same number and kinds of chromosomes. But mitosis is only one phase during the life of a dividing cell. The entire sequence of events that a cell goes through from its origin in the division of its parent cell through its own division into two daughter cells is called the cell cycle (Figure 19.2). The cell cycle consists of two major phases: interphase and cell division.

FIGURE 19.2. The cell cycle

Interphase is the period of the cell cycle between cell divisions. It accounts for most of the time that elapses during a cell cycle. During active growth and divisions (depending on the type of cell), an entire cell cycle might take about 16 to 24 hours to complete, and only 1 to 2 hours are spent in division. Interphase is not a "resting period," as once thought. Instead, interphase is a time when the cell carries out its functions and grows. If the cell is going to divide, interphase is a time of intense preparation for cell division. During interphase, the DNA and organelles are duplicated. These preparations ensure that when the cell divides, each of its resulting cells, called daughter cells, will receive the essentials for survival.

Interphase consists of three parts: G1 (first "gap"), S (DNA synthesis), and G2 (second "gap"). All three parts of interphase are times of cell growth, characterized by the production of organelles and the synthesis of proteins and other macromolecules. There are, however, some events specific to certain parts of interphase:

• G1: A time of major growth before DNA synthesis begins.

• S: The time during which DNA is synthesized (replicated).

• G2: A time of growth after DNA is synthesized and before mitosis begins.

The details of DNA synthesis (replication) are described in Chapter 21. Our discussion in this chapter introduces some basic terminology pertaining to the cell cycle.

Throughout interphase, the genetic material is in the form of long, thin threads that are often called chromatin (Figure 19.3). They twist randomly around one another like tangled strands of yarn. In this state, DNA can be synthesized (replicated) and genes can be active. At the start of interphase, during G1, each chromosome consists of a DNA molecule and proteins. When the chromosomes are being replicated during the S phase, the chromosome copies remain attached. The two copies, each an exact replicate of the original chromosome, stay attached to one another at a region called the centromere. As long as the replicate copies remain attached, each copy is called a chromatid. The two attached chromatids are genetically identical and are called sister chromatids.

FIGURE 19.3. Changes in chromosome structure because of DNA replication during interphase and preparation for nuclear division in mitosis

Describe the difference in the structure of a chromosome between the start of interphase and at the end of interphase.

At the start of interphase, a chromosome is a single strand of DNA. At the end of interphase, a chromosome consists of two sister chromatids that are replicate copies of the original strand of DNA.

Division of the Nucleus and the Cytoplasm

Body cells divide continually in the developing embryo and fetus. Such division also plays an important role in the growth and repair of body tissues in children. In the adult, specialized cells, such as most nerve cells, lose their ability to divide. Late in G1 of interphase, these cells enter what is called the G0 stage they are carrying out their normal cellular activities but do not divide. Other adult cells, such as liver cells, stop dividing but retain the ability to undergo cell division should the need for tissue repair and replacement arise. Still other cells actively divide throughout life. For example, the ongoing cell division in skin cells in adults serves to replace the enormous numbers of cells worn off each day.

We see, then, that the cell cycle requires precise timing and accuracy. Proteins monitor the environment within the cell to ensure that it is appropriate for cell division and that the DNA has been accurately replicated. Healthy cells will not divide unless these two conditions are met. However, as we will see in Chapter 21a, cancer cells escape this regulation and divide uncontrollably.

The division of body cells (after interphase) consists of two processes that overlap somewhat in time. The first process, division of the nucleus, is called mitosis. The second process is cytokinesis, which is the division of the cytoplasm that occurs toward the end of mitosis (Figure 19.4).

FIGURE 19.4. An overview of mitosis

Mitosis: Creation of Genetically Identical Diploid Body Cells

For the purpose of discussion, mitosis is usually divided into four stages: prophase, metaphase, anaphase, and telophase. The major events of each stage are depicted in Figure 19.5 (pp. 396-397).

• Prophase Mitosis begins with prophase, a time when changes occur in the nucleus as well as the cytoplasm. In the nucleus, the chromatin condenses and forms chromosomes as DNA wraps around histones. The DNA then loops and twists to form a tightly compacted structure (see Figure 19.3). When DNA is in this condensed state, it cannot be replicated, and gene activity is shut down. In this condensed state, the sister chromatids are easier to separate without breaking. At about this time, the nuclear membrane also begins to break down.

FIGURE 19.5. The stages of cell division (mitosis and cytokinesis) captured In light micrographs and depicted in schematic drawings

Outside the nucleus, in the cytoplasm, the mitotic spindle forms. The mitotic spindle is made of microtubules associated with the centrioles (see Chapter 3). During prophase, the centrioles, duplicated during interphase, move away from each other toward opposite ends of the cell.

• Metaphase During the next stage of mitosis, metaphase, the chromosomes attach to the mitotic spindles, forming a line at what is called the equator (center) of the mitotic spindles. This alignment ensures each daughter cell receives one chromatid from each of the 46 chromosomes when the chromosomes separate at the centromere. Thus each daughter cell is a diploid cell that is genetically identical to the parent cell.

• Anaphase Anaphase begins when the sister chromatids of each chromosome begin to separate, splitting at the centromere. Now separate entities, the sister chromatids are considered chromosomes in their own right. The spindle fibers pull the chromosomes toward opposite poles of the cell. By the end of anaphase, equivalent collections of chromosomes are located at the two poles of the cell.

• Telophase During telophase, a nuclear envelope forms around each group of chromosomes at each pole, and the mitotic spindle disassembles. The chromosomes also become more threadlike in appearance.

Cancer cells divide rapidly and without end. One type of drug used in cancer chemotherapy inhibits the formation of spindle fibers. Why can this be an effective anticancer treatment?

Cytokinesis—division of the cytoplasm—begins toward the end of mitosis, sometime during telophase. During this period, a band of microfilaments in the area where the chromosomes originally aligned contracts and forms a furrow, as shown in Figure 19.6. The furrow deepens, eventually pinching the cell in two.

FIGURE 19.6. Cytokinesis is the division of the cytoplasm to form two daughter cells.

What would happen if a cell completed mitosis but did not complete cytokinesis?

As we have seen, a major feature of cell division is the shortening and thickening of the chromosomes. In this state, the chromosomes are visible with a light microscope and can be used for diagnostic purposes, such as when potential parents want to check their own chromosomal makeup for defects. One often-used method takes white blood cells from a blood sample and grows them for a while in a nourishing medium. The culture then is treated with a drug that destroys the mitotic spindle, thus preventing separation of the chromosomes and halting cell division at metaphase. Next the cells are fixed, stained, and photographed so that the images of the chromosomes can be arranged in pairs based on physical characteristics such as location of the centromere and overall length. The chromosomes are numbered from largest to smallest, in an arrangement called a karyotype (Figure 19.7). Karyotypes can be checked for irregularities in number or structure of chromosomes.

FIGURE 19.7. Chromosomes in dividing cells can be examined for defects in number or structure. A karyotype is constructed by arranging the chromosomes from photographs based on size and centromere location.

Meiosis: Creation of Haploid Gametes

We have seen that the somatic cells contain a homologous pair of each type of chromosome, one member of each pair from the father and one member of each pair from the mother. Recall that a cell with homologous pairs of chromosomes is described as being diploid, 2n. The gametes—eggs or sperm—differ from somatic cells in that they are haploid, indicated by n, meaning that they have only one member of each homologous pair of chromosomes. As you read earlier in the chapter, gametes are produced by a type of cell division called meiosis, which is actually two divisions that result in up to four haploid daughter cells. When a sperm fertilizes an egg, a new cell—the zygote—is created. Because the egg and sperm both contribute a set of chromosomes to the zygote, it is diploid. After many mitotic cell divisions, a zygote can eventually develop into a new individual.

Meiosis serves two important functions in sexual reproduction:

• Meiosis keeps the number of chromosomes in a body cell constant from generation to generation.

• Meiosis increases genetic variability in the population.

Meiosis keeps the number of chromosomes in a body cell constant over generations because it creates haploid gametes (sperm and eggs) with only one member of each homologous pair of chromosomes. If gametes were produced by mitosis, they would be diploid each sperm and egg would contain 46 chromosomes instead of 23. Then, if a sperm containing 46 chromosomes fertilized an egg with 46 chromosomes, the zygote would have 92 chromosomes. The zygote of the next generation would have 184 chromosomes, having been formed by an egg and sperm each containing 92 chromosomes. The next generation would have 368 chromosomes in each cell, and the next one 736—and so on. You can see that the chromosome number would quickly become unwieldy and, what is more important, alter the amount of genetic information in each cell. As we will see toward the chapter's end, even one extra copy of a single chromosome usually causes an embryo to die.

Meiosis also increases genetic variability in the population. Later in this chapter we consider the mechanisms by which it accomplishes this increase. Genetic variability is important because it provides the raw material through which natural selection can act, leading to the changes described collectively as evolution. The relationship between genetic variability and evolution is discussed in Chapter 22.

Two Meiotic Cell Divisions: Preparation for Sexual Reproduction

First, let's consider how meiosis keeps the chromosome number constant. The stages in meiosis are summarized in Figure 19.8. Meiosis and mitosis begin the same way. Both are preceded by the same event—the replication of chromosomes. Unlike mitosis, however, meiosis involves two divisions. In the first division, the chromosome number is reduced, because the two homologues of each pair of chromosomes (each replicated into two chromatids attached by a centromere) are separated into two cells so that each cell has one member of each homologous pair of chromosomes. In the second division, the replicated chromatids of each chromosome are separated. We see, then, that meiosis begins with one diploid cell and, two divisions later, produces four haploid cells. The orderly movements of chromosomes during meiosis ensure that each haploid gamete produced contains one member of each homologous pair of chromosomes. Although not shown in the summary figure, each of the two meiotic divisions has four stages similar to those in mitosis: prophase, metaphase, anaphase, and telophase.

FIGURE 19.8. Overview of meiosis. Meiosis reduces the chromosome number from the diploid number to the haploid number. Meiosis involves two cell divisions.

Meiosis I . The first meiotic division—meiosis I—produces two cells, each with 23 chromosomes. Note that the daughter cells do not contain a random assortment of any 23 chromosomes. Instead, each daughter cell contains one member of each homologous pair, with each chromosome consisting of two sister chromatids.

It is important that each daughter cell receive one of each kind of chromosome during meiosis I. If one of the daughter cells had two of chromosome 3 and no chromosome 6, it would not survive. Although there would still be 23 chromosomes present, part of the instructions for the structure and function of the body (chromosome 6) would be missing. The separation of homologous chromosomes occurs reliably during meiosis I because, during prophase I (the I indicates this phase takes place during meiosis I), members of homologous pairs line up next to one another by a phenomenon called synapsis ("bringing together"). For example, the chromosome 1 that was originally from your father would line up with the chromosome 1 originally from your mother. Paternal chromosome 2 would pair with maternal chromosome 2, and so on. During metaphase I, matched homologous pairs become positioned at the midline of the cell and attach to spindle fibers. The pairing of homologous chromosomes helps ensure that the daughter cells will receive one member of each homologous pair. Consider the following analogy. By pairing your socks before putting them in a drawer, you are more likely to put matching socks on your feet than if you randomly pulled out two socks.

Next, during anaphase I, the members of each homologous pair of chromosomes separate, and each homologue moves to opposite ends of the cell. During telophase I, cytokinesis begins, resulting in two daughter cells, each with one member of each chromosome pair. Each chromosome in each daughter cell still consists of two replicated sister chromatids. Telophase I is followed by interkinesis, a brief interphase-like period. Interkinesis differs from mitotic interphase in that there is no replication of DNA during interkinesis.

Meiosis II During the second meiotic division—meiosis II— each chromosome lines up in the center of the cell independently (as occurs in mitosis), and the sister chromatids (attached replicates) making up each chromosome separate. Separation of the sister chromatids occurs in both daughter cells that were produced in meiosis I. This event results in four cells, each containing one of each kind of chromosome. The events of meiosis II are similar to those of mitosis, except that only 23 chromosomes are lining up independently in meiosis II compared with the 46 chromosomes aligning independently in mitosis. Figure 19.9 depicts the events of meiosis. Table 19.1 and Figure 19.10 compare mitosis and meiosis.

FIGURE 19.9. Stages of meiosis

TABLE 19.1. Mitosis and Meiosis Compared

Involves one cell division

Involves two cell divisions

Produces two diploid cells

Produces up to four haploid cells

Occurs only in ovaries and testes during the formation of gametes (egg and sperm)

Results in growth and repair

Results in gamete (egg and sperm) production

No exchange of genetic material

Parts of chromosomes are exchanged in crossing over

Daughter cells are genetically similar

Daughter cells are genetically dissimilar

FIGURE 19.11. Comparison of spermatogenesis and oogenesis. Meiosis results in haploid cells that differentiate into mature gametes. Spermatogenesis produces four sperm cells that are specialized to transport the male’s genetic information to the egg. Oogenesis produces up to three polar bodies and one ovum that is packed with nutrients to nourish the early embryo.

Genetic Variability: Crossing Over and Independent Assortment

At the moment of fertilization, when the nuclei of an egg and a sperm fuse, a new, unique individual is formed. Although certain family characteristics may be passed along, each child bears its own assortment of genetic characteristics (Figure 19.12).

FIGURE 19.12. Each child inherits a unique combination of maternal and paternal genetic characteristics due to the shuffling of chromosomes that occurs during meiosis. This photograph shows Eric and Mary Goodenough with their four sons: Derick, Stephen, David, and John.

Genetic variation arises largely because of the shuffling of maternal and paternal forms of genes during meiosis. One way this mixing occurs is through a process called crossing over, in which corresponding pieces of chromatids of maternal and paternal homologues (nonsister chromatids) are exchanged during synapsis when the homologues are aligned side by side. After crossing over, the affected chromatids have a mixture of DNA from the two parents. Because the homologues align gene by gene during synapsis, the exchanged segments contain genetic information for the same traits. However, because the genes of the mother and those of the father may direct different expressions of the trait—attached or unattached earlobes, for instance—the chromatids affected by crossing over have a new, novel combination of genes. Thus, crossing over increases the genetic variability of gametes (Figure 19.13).

FIGURE 19.13. Crossing over. During synapsis, when the homologous chromosomes of the mother and the father are closely aligned, corresponding segments of nonsister chromatids are exchanged. Each of the affected chromatids has a mixture of maternal and paternal genetic information.

Independent assortment is a second way that meiosis provides for the shuffling of genes between generations (Figure 19.14). Recall that the homologous pairs of chromosomes line up at the equator (midpoint) of the mitotic spindles during metaphase I. However, the orientation of the members of the pair is random with respect to which member is closer to which pole. Thus, like the odds that a flipped coin will come up heads, there is a fifty-fifty chance that a given daughter cell will receive the maternal chromosome from a particular pair. Each of the 23 pairs of chromosomes orients independently during metaphase I. The orientations of all 23 pairs will determine the assortments of maternal and paternal chromosomes in the daughter cells. Thus, each child (other than identical siblings) of the same parents has a unique genetic makeup.

FIGURE 19.14. Independent assortment. The relative positioning of homologous maternal and paternal chromosomes with respect to the poles of the cell is random. The members of each homologous pair orient independently of the other pairs. Notice that with only two homologous pairs, there are four possible combinations of chromosomes in the resulting gametes.

Extra or Missing Chromosomes

Most of the time, meiosis is a precise process that results in the chromosomes being distributed evenly to gametes. But meiosis is not foolproof. A pair of chromosomes or sister chromatids may adhere so tightly to one another that they do not separate during anaphase. As a result, both go to the same daughter cell, and the other daughter cell receives none of this type of chromosome (Figure 19.15). The failure of homologous chromosomes to separate during meiosis I or of sister chromatids to separate during meiosis II is called nondisjunction.

FIGURE 19.15. Nondisjunction is a mistake that occurs during cell division in which homologous chromosomes or sister chromatids fail to separate during anaphase. One of the resulting daughter cells will have three of one type of chromosome, and the other daughter cell will be missing that type of chromosome.

One in every 700 infants is born with three copies of chromosome 21 (trisomy 21), a condition known as Down syndrome. Symptoms of Down syndrome include moderate to severe mental retardation, short stature or shortened body parts due to poor skeletal growth, and characteristic facial features (Figure 19.A). Individuals with Down syndrome typically have a flattened nose, a forward-protruding tongue that forces the mouth open, upward-slanting eyes, and a fold of skin at the inner corner of each eye. Approximately 50% of all infants with Down syndrome have heart defects, and many of them die as a result of this defect. Blockage in the digestive system, especially in the esophagus or small intestine, is also common and may require surgery shortly after birth.

FIGURE 19.A. A person with Down syndrome is moderately to severely mentally retarded and has a characteristic appearance.

The risk of having a baby with Down syndrome increases with the mother's age. A 30-year-old woman is twice as likely to give birth to a child with Down syndrome as is a 20-year-old woman. After age 30, the risk rises dramatically. At age 45, a mother is 45 times as likely to give birth to a Down syndrome infant as is a 20-year-old woman.

Today, people with Down syndrome live longer and with a higher quality life than they did in the past. These improvements are due to better healthcare, more effective teaching approaches, and a greater range of opportunities. Life expectancy is now approaching 60 years in many countries.

Prenatal screening for Down syndrome is common and usually recommended for pregnant women aged over 30 years. Approximately 95% of the “positive” screening tests are wrong. Nonetheless, allwomen who initially test positive for carrying a fetus with Down syndrome are encouraged to undergo more invasive tests and 1% to 2% of the pregnancies tested by these procedures result in miscarriage. As a result, prenatal screening for Down syndrome poses a risk to 700,000 pregnancies each year.

Questions to Consider

Down Syndrome International is encouraging reviews of screening policies and public debate about the acceptance of genetic screening for mental and physical disabilities.

• If you or a loved one were pregnant, would you advocate for prenatal screening for Down syndrome? Why or why not?

• Who should pay for prenatal screening? The person? Health insurer? The government?

• Do you agree that genetic screening for mental and physical disabilities should be recommended?

What happens if nondisjunction creates a gamete with an extra or a missing chromosome and that gamete is then united with a normal gamete during fertilization? The resulting zygote will have an excess or deficit of chromosomes. For instance, if the abnormal gamete has an extra chromosome, the resulting zygote will have three of one type of chromosome and two of the rest. This condition, in which there are three representatives of one chromosome, is called trisomy. If, on the other hand, a gamete that is missing a representative of one type of chromosome joins with a normal gamete during fertilization, the resulting zygote will have only one of that type of chromosome, rather than the normal two chromosomes. The condition in which there is only one representative of a particular chromosome in a cell is called monosomy. The imbalance of chromosome numbers usually causes abnormalities in development. Most of the time, the resulting malformations are severe enough to cause the death of the fetus, which will result in a miscarriage. Indeed, in about 70% of miscarriages, the fetus has an abnormal number of chromosomes.

When a fetus inherits an abnormal number of certain chromosomes—for instance, chromosome 21 or the sex chromosomes—the resulting condition is usually not fatal (see Ethical Issue essay, Trisomy 21). The upset in chromosome balance does, however, cause a specific syndrome. (A syndrome is a group of symptoms that generally occur together.)

Like autosomes, sex chromosomes may fail to separate during anaphase. This error can occur during either egg or sperm formation. A male is chromosomally XY, so when the X and Y separate during anaphase, equal numbers of X-bearing and Y-bearing sperm are produced. However, if nondisjunction of the sex chromosomes occurs during sperm formation, half of the resulting sperm will carry both X and Y chromosomes, whereas the other resulting sperm will not contain any sex chromosome. A female is chromosomally XX, so each of the eggs she produces should contain a single X chromosome. When nondisjunction of sex chromosomes occurs, however, an egg may contain two X chromosomes or none at all. When a gamete with an abnormal number of sex chromosomes is joined with a normal gamete during fertilization, the resulting zygote has an abnormal number of sex chromosomes (Figure 19.16).

FIGURE 19.16. The sex chromosomes may fail to separate during formation of a gamete. Here an egg with an abnormal number of sex chromosomes joins a normal sperm in fertilization the resulting zygote has an abnormal number of sex chromosomes. Imbalances of sex chromosomes upset normal development of reproductive structures.

Turner syndrome occurs in individuals who have only a single X chromosome (XO). Approximately 1 in 5000 female infants is born with Turner syndrome, but this represents only a small percentage of the XO zygotes that are formed. Most of these XO zygotes are lost as miscarriages. A person with Turner syndrome has the external appearance of a female. The only hint of Turner syndrome may be a thick fold of skin on the neck. As she ages, however, she generally is noticeably shorter than her peers. Her chest is wide, and her breasts underdeveloped. In 90% of the women with Turner syndrome, the ovaries are also poorly developed, leading to infertility. Pregnancy may be possible through in vitro fertilization (see Chapter 18), in which a fertilized egg from a donor is implanted in her uterus.

Klinefelter syndrome is observed in males who are XXY. Although the extra X chromosome can be inherited as a result of nondisjunction during either egg or sperm formation, it is twice as likely to come from the egg. Increased maternal age may increase the risk slightly.

Klinefelter syndrome is fairly common. Approximately 1 in 500 to 1 in 1000 of all newborn males is XXY. However, not all XXY males display the symptoms of having an extra X chromosome. In fact, some of them live their lives without ever suspecting that they are XXY. When there are signs that a male has Klinefelter syndrome, they do not usually show up until puberty. During the teenage years, the testes of an XY male gradually increase in size. In contrast, the testes of many XXY males remain small and do not produce an adequate amount of the male sex hormone, testosterone. As a result of the testosterone insufficiency, these males may grow taller than average but remain less muscular. Secondary sex characteristics, such as facial and body hair, may fail to develop fully. The breasts may also develop slightly. The penis is usually of normal size, but the testes may not produce sperm so men with Klinefelter syndrome may be sterile.

Nondisjunction can also result in a female with three X chromosomes (XXX, triple-X syndrome) or a male with two Y chromosomes (XYY, Jacob syndrome, produced when the chromatids of a replicated Y chromosome fail to separate). Most women with triple-X syndrome (XXX) have normal sexual development and are able to conceive children. Some triple-X females have learning disabilities and delayed language skills. Males with two Y chromosomes (XYY) are often taller than normal, and some have slightly lower than normal intelligence.

If you had a son with Klinefelter syndrome, would you want him to have testosterone treatments after puberty?

In this chapter we considered cell division: mitosis, which gives rise to new body cells for growth and repair, and meiosis, which gives rise to the gametes (eggs and sperm). In the next chapter, we consider mitosis further and explore stem cells, which are unspecialized cells that can divide continuously and develop into different tissue types.

Highlighting the Concepts

Two Types of Cell Division (p. 392)

• The human life cycle requires two types of nuclear division— mitosis and meiosis. Mitosis creates cells that are exact copies of the original cell. Mitosis occurs in growth and repair. Meiosis creates cells with half the number of chromosomes as were in the original cell. Gamete production requires meiosis.

Form of Chromosomes (p. 393)

• A chromosome contains DNA and proteins called histones. A gene is a segment of DNA that codes for a protein that plays a structural or functional role in the cell. Genes are arranged along a chromosome in a specific order. Each of the 23 different kinds of chromosomes in human cells contains a specific sequence of genes.

• Somatic cells (all cells except for eggs and sperm) are diploid that is, they contain pairs of chromosomes, one member of each pair from each parent. Homologous chromosomes carry genes for the same traits. In humans, the diploid number of chromosomes is 46—or 23 homologous pairs. One pair of chromosomes, the sex chromosomes, determines gender. Males are XY, and females are XX. The other 22 pairs of chromosomes are called autosomes. Eggs and sperm are haploid they contain only one set of chromosomes.

• The cell cycle consists of two major phases: interphase and cell division. Interphase is the period between cell divisions.

• During interphase, DNA and organelles become replicated in preparation for the cell to divide and produce two identical daughter cells. Somatic cell division consists of mitosis (division of the nucleus) and cytokinesis (division of the cytoplasm).

Mitosis: Creation of Genetically Identical Diploid Body Cells (pp. 394-398)

• In mitosis, the original cell, having replicated its genetic material, distributes it equally between its two daughter cells. There are four stages of mitosis: prophase, metaphase, anaphase, and telophase.

• Cytokinesis, division of the cytoplasm, usually begins sometime during telophase. A band of microfilaments at the midline of the cell contracts and forms a furrow. The furrow deepens and eventually pinches the cell in two.

• A karyotype is an arrangement of chromosomes based on their physical characteristics, such as length and position of the centromere.

Meiosis: Creation of Haploid Gametes (pp. 398-407)

• Meiosis, a special type of nuclear division that occurs in the ovaries or testes, begins with a diploid cell and produces four haploid cells that will become gametes (eggs or sperm).

• Meiosis is important because it halves the number of chromosomes in gametes, thereby keeping the chromosome number constant between generations. When a sperm fertilizes an egg, a diploid cell called a zygote is created. After many successful mitotic divisions, the zygote may develop into a new individual.

• Before meiosis begins, the chromosomes are replicated, and the copies remain attached to one another by centromeres. The attached replicated copies are called sister chromatids.

• There are two cell divisions in meiosis. During the first meiotic division (meiosis I), members of homologous pairs are separated. Thus, the daughter cells contain only one member of each homologous pair (although each chromosome still consists of two replicated sister chromatids). During the second meiotic division (meiosis II), the sister chromatids are separated.

• Genetic recombination during meiosis results in variation among offspring from the same two parents. One cause of genetic recombination is crossing over, in which corresponding segments of DNA are exchanged between maternal and paternal homologues, creating new combinations of genes in the resulting chromatids.

• A second cause of genetic recombination is the independent assortment of maternal and paternal homologues into daughter cells during meiosis I. The orientation of the members of the pair relative to the poles of the cell determines whether a daughter cell will receive the maternal or the paternal chromosome from a given pair. Each pair aligns independently of the others.

• Nondisjunction is the failure of homologous chromosomes or sister chromatids to separate during cell division. It results in an abnormal number of chromosomes in the resulting gametes, and in zygotes created by fertilization involving these gametes, which generally results in death of the fetus. Nondisjunction of chromosome 21 can result in Down syndrome.

1. Explain the relationship between genes and a chromosome. р. 393

2. Define mitosis and cytokinesis. pp. 394-398

3. Why is meiosis important? p. 398

4. Describe the alignment of chromosomes at the midline during meiosis I and meiosis II. Explain the importance of these alignments in creating haploid gametes from diploid cells. pp. 400-403

5. Explain how crossing over and independent assortment result in genetic recombination that causes variability among offspring (aside from identical twins) from the same two parents. pp. 403-404

6. Define nondisjunction. Explain how nondisjunction can result in abnormal numbers of chromosomes in a person. p. 405

7. What causes Down syndrome? What are the usual characteristics of the condition? p. 405

8. The process of mitosis results in

9. DNA is synthesized (replicated) during

10. Crossing over occurs during which stage of meiosis?

11. During meiosis, the processes of _____ and _____ increase genetic diversity.

12. _____ chromosomes carry genes for the same traits.

13. _____ is the pairing of chromosomes during meiosis.

14. The stage of mitosis during which sister chromatids separate is _____.

15. The stage of meiosis during which sister chromatids separate is _____.

Applying the Concepts

1. A cell biologist is studying the cell cycle. She is growing the cells in culture, and they are actively dividing mitotically. One particular cell has half as much DNA as most of the other cells. Which stage of mitosis is this cell in? How do you know?

2. What would happen if the spindle fibers failed to form during mitosis?

3. What condition is indicated by the following karyotype?

Becoming Information Literate

Several genetic disorders are caused by too many or too few chromosomes. Use at least three reliable sources (books, journals, websites) to describe at least one such disorder other than Down syndrome, Turner syndrome, and Klinefelter syndrome. Indicate which chromosomes are extra or missing in the disorder, and note the symptoms of the disorder. List each source you considered, and explain why you chose the three sources you used.

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Conclusions

DNA methylation patterns of imprinted genes as well as germ cell marker genes are already in place and remain stable throughout spermatogenesis in normal samples. Interestingly, XIST shows a pattern of regulation that distinguishes the germline from somatic tissues. This gene, which is regularly fully methylated in normal males, shows a completely unmethylated status in undifferentiated germ cells as well as sperm. Individual Klinefelter men showed the presence of a population of germ cells with normal transcription as well as DNA methylation patterns for germ cell markers. In stark contrast, imprinted genes did not show the expected patterns of DNA methylation, indicating that the germline from these men might present imprinting aberrations.


Deleting chromosomes

When turning tissue from the ear of XXY (and XYY) mice into connective tissue knows as fibroblasts and subsequently into stem cells (cells that can produce indefinitely more cells), the scientists behind the new research noticed that some of the cells lost the extra sex chromosome. They also showed that this kind of chromosome loss happens when reprogramming human cells that have three instances of a particular chromosome, instead of the normal two.

Subsequently, they developed an experimental cocktail to produce germ cells from these stem cells in a lab dish. However, to produce fully functional sperm it was necessary to place these germ cells into the testicles of a male mouse. Remarkably, these sperm were fertile. When injected into eggs, they created healthy, fertile offspring free of the chromosomal abnormality.

The research boosts hopes that men with Klinefelter’s syndrome, for example, would be able to produce sperm and healthy offspring in cases where they don’t actually produce any sperm. The researchers showed similar chromosome loss in mice with the equivalent of Down’s syndrome. This is exciting, as men and women with Down’s syndrome tend to have lower fertility and have a high risk of their children having Down’s syndrome, too. In fact people with a number of genetic conditions that are associated with infertility may one day be helped by the technique.

There are a number of substantial challenges to overcome for this to be realised in humans. The toughest one will be to produce functional germ cells outside the human body. We are still very much at the early stages of understanding these processes.

It will also be challenging to determine when to start human experiments. In the UK, we have a strict but permissive legislative framework for generating human embryos for research. As such, under research procedures, we would have to determine the viability, genetic and epigenetic profile of a blastocyst (a structure of cells formed in the early development of the fetus) created from germ cells in the lab. As long as these are normal then the next steps are to proceed to implantation of the embryos into the woman.

We are undoubtedly a long way from achieving this, but truly breath-taking progress is being made in the area of stem cell and germ cell biology. Coupled with a highly efficient reproductive medicine scene and permissive regulations, we are well placed to address the challenges of translating this exciting research into humans.