Klinefelter syndrome (KS), also known as 47,XXY, is an
aneuploid genetic condition
A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosomal abnormality. Although polygenic disorders ...
where a male has an additional copy of the
X chromosome
The X chromosome is one of the two sex-determining chromosomes ( allosomes) in many organisms, including mammals (the other is the Y chromosome), and is found in both males and females. It is a part of the XY sex-determination system and XO se ...
.
The primary features are
infertility
Infertility is the inability of a person, animal or plant to reproduce by natural means. It is usually not the natural state of a healthy adult, except notably among certain eusocial species (mostly haplodiploid insects). It is the normal st ...
and small, poorly functioning
testicles
A testicle or testis (plural testes) is the male reproductive gland or gonad in all bilaterians, including humans. It is homologous to the female ovary. The functions of the testes are to produce both sperm and androgens, primarily testostero ...
.
Usually, symptoms are subtle and subjects do not realize they are affected.
Sometimes, symptoms are more evident and may include weaker muscles, greater height, poor
motor coordination Motor coordination is the orchestrated movement of multiple body parts as required to accomplish intended actions, like walking. This coordination is achieved by adjusting kinematic and kinetic parameters associated with each body part involved i ...
, less body hair,
breast growth, and less interest in sex.
Often, these symptoms are noticed only at
puberty
Puberty is the process of physical changes through which a child's body matures into an adult body capable of sexual reproduction. It is initiated by hormonal signals from the brain to the gonads: the ovaries in a girl, the testes in a b ...
.
Intelligence is usually normal, but
reading difficulties and problems with speech are more common.
Klinefelter syndrome occurs randomly.
[ The extra X chromosome comes from the father and mother nearly equally.] An older mother may have a slightly increased risk of a child with KS.[ The syndrome is defined by the presence of at least one extra X chromosome in addition to a ]Y chromosome
The Y chromosome is one of two sex chromosomes ( allosomes) in therian mammals, including humans, and many other animals. The other is the X chromosome. Y is normally the sex-determining chromosome in many species, since it is the presence or a ...
yielding a total of 47 or more chromosome
A chromosome is a long DNA molecule with part or all of the genetic material of an organism. In most chromosomes the very long thin DNA fibers are coated with packaging proteins; in eukaryotic cells the most important of these proteins ar ...
s rather than the usual 46. KS is diagnosed by the genetic test known as a karyotype
A karyotype is the general appearance of the complete set of metaphase chromosomes in the cells of a species or in an individual organism, mainly including their sizes, numbers, and shapes. Karyotyping is the process by which a karyotype is disce ...
.[
While no cure is known, a number of treatments may help.][ Physical therapy, occupational therapy, speech and language therapy, ]counselling
Counseling is the professional guidance of the individual by utilizing psychological methods especially in collecting case history data, using various techniques of the personal interview, and testing interests and aptitudes.
This is a list of co ...
, and adjustments of teaching methods may be useful.[ Testosterone replacement may be used in those who have significantly lower levels.][ Enlarged breasts may be removed by surgery.][ About half of affected males have a chance of fathering children with the help of ]assisted reproductive technology
Assisted reproductive technology (ART) includes medical procedures used primarily to address infertility. This subject involves procedures such as in vitro fertilization (IVF), intracytoplasmic sperm injection (ICSI), cryopreservation of gametes o ...
, but this is expensive and not risk free. XXY males have a ~15-fold higher risk of developing breast cancer than typical, but still lower than that of females. People with the condition have a nearly normal life expectancy
Life expectancy is a statistical measure of the average time an organism is expected to live, based on the year of its birth, current age, and other demographic factors like sex. The most commonly used measure is life expectancy at birth ...
.
Klinefelter syndrome is one of the most common chromosomal disorders, occurring in one to two per 1,000 live male births. It is named after American endocrinologist Harry Klinefelter, who identified the condition in the 1940s. In 1956, the extra X chromosome was identified as the cause. Mice can also have the XXY syndrome, making them a useful research model.
Signs and symptoms
The primary features are infertility
Infertility is the inability of a person, animal or plant to reproduce by natural means. It is usually not the natural state of a healthy adult, except notably among certain eusocial species (mostly haplodiploid insects). It is the normal st ...
and small, poorly functioning testicles
A testicle or testis (plural testes) is the male reproductive gland or gonad in all bilaterians, including humans. It is homologous to the female ovary. The functions of the testes are to produce both sperm and androgens, primarily testostero ...
. Often, symptoms may be subtle and many people do not realize they are affected.[ Sometimes, symptoms are more prominent and may include weaker muscles, greater height, poor ]coordination
Coordination may refer to:
* Coordination (linguistics), a compound grammatical construction
* Coordination complex, consisting of a central atom or ion and a surrounding array of bound molecules or ions
* Coordination number or ligancy of a centr ...
, less body hair, breast growth, and low libido.[ Often, these symptoms are noticed only at ]puberty
Puberty is the process of physical changes through which a child's body matures into an adult body capable of sexual reproduction. It is initiated by hormonal signals from the brain to the gonads: the ovaries in a girl, the testes in a b ...
.[
]
Prenatal
An estimated 60% of fetuses with Klinefelter syndrome end in miscarriage.
Physical
As babies and children, XXY males may have weaker muscles and reduced strength. As they grow older, they tend to become taller than average. They may have less muscle control and coordination than other boys of their age.[
During puberty, the physical traits of the syndrome become more evident; because these boys do not produce as much testosterone as other boys, they have a less muscular body, less facial and body hair, and broader hips. As teens, XXY males may develop breast tissue and also have weaker bones, and a lower energy level than other males.][
By adulthood, XXY males look similar to males without the condition, although they are often taller. In adults, possible characteristics vary widely and include little to no sign of affectedness, a lanky, youthful build and facial appearance, or a rounded body type with some degree of ]gynecomastia
Gynecomastia (also spelled gynaecomastia) is the abnormal non-cancerous enlargement of one or both breasts in males due to the growth of breast tissue as a result of a hormone imbalance between estrogens and androgens. Updated by Brent Wisse ...
(increased breast tissue). Gynecomastia is present in about a third of affected individuals, a slightly higher percentage than in the XY population. About 10% of XXY males have gynecomastia noticeable enough that they may choose to have cosmetic surgery.
Affected males are often infertile, or have reduced fertility. Advanced reproductive assistance is sometimes possible. An estimated 50% of males with Klinefelter syndrome can produce sperm.
The term "hypogonadism
Hypogonadism means diminished functional activity of the gonads—the testes or the ovaries—that may result in diminished production of sex hormones. Low androgen (e.g., testosterone) levels are referred to as hypoandrogenism and low est ...
" in XXY symptoms is often misinterpreted to mean "small testicles", when it instead means decreased testicular hormone/endocrine function. Because of (primary) hypogonadism, individuals often have a low serum testosterone
Testosterone is the primary sex hormone and anabolic steroid in males. In humans, testosterone plays a key role in the development of male reproductive tissues such as testes and prostate, as well as promoting secondary sexual characteris ...
level, but high serum follicle-stimulating hormone
Follicle-stimulating hormone (FSH) is a gonadotropin, a glycoprotein polypeptide hormone. FSH is synthesized and secreted by the gonadotropic cells of the anterior pituitary gland and regulates the development, growth, pubertal maturation, ...
and luteinizing hormone
Luteinizing hormone (LH, also known as luteinising hormone, lutropin and sometimes lutrophin) is a hormone produced by gonadotropic cells in the anterior pituitary gland. The production of LH is regulated by gonadotropin-releasing hormone (Gn ...
levels, hypergonadotropic hypogonadism. Despite this misunderstanding of the term, however, XXY men may also have microorchidism
Microorchidism is a genetic disorder found in males, characterized by abnormally small testes; it is the opposite of macroorchidism, which is characterized by abnormally large testes. The condition is associated with (and often secondary to) a numb ...
(i.e., small testicles).
The testicles of affected males are usually less than 2 cm in length (and always shorter than 3.5 cm), 1 cm in width, and 4 ml in volume.
XXY males are more likely than other men to have certain health problems, such as autoimmune disorders, breast cancer
Breast cancer is cancer that develops from breast tissue. Signs of breast cancer may include a lump in the breast, a change in breast shape, dimpling of the skin, milk rejection, fluid coming from the nipple, a newly inverted nipple, or ...
, venous thromboembolic disease
Venous thrombosis is blockage of a vein caused by a thrombus (blood clot). A common form of venous thrombosis is deep vein thrombosis (DVT), when a blood clot forms in the deep veins. If a thrombus breaks off (embolizes) and flows to the lungs to ...
, and osteoporosis. In contrast to these potentially increased risks, rare X-linked recessive
X-linked recessive inheritance is a mode of inheritance in which a mutation in a gene on the X chromosome causes the phenotype to be always expressed in males (who are necessarily homozygous for the gene mutation because they have one X and one ...
conditions are thought to occur less frequently in XXY males than in XY males, since these conditions are transmitted by genes on the X chromosome, and people with two X chromosomes are typically only carriers rather than affected by these X-linked recessive conditions.
Cognitive and developmental
Some degree of language learning or reading impairment may be present, and neuropsychological testing often reveals deficits in executive functions
In cognitive science and neuropsychology, executive functions (collectively referred to as executive function and cognitive control) are a set of cognitive processes that are necessary for the cognitive control of behavior: selecting and succ ...
, although these deficits can often be overcome through early intervention. Also, delays in motor development may occur, which can be addressed through occupational and physical therapies. XXY males may sit up, crawl, and walk later than other infants; they may also struggle in school, both academically and with sports. It is estimated that 10% of those with Klinefelter syndrome are autistic.
Additional abnormalities may include impaired attention, reduced organizational and planning abilities, deficiencies in judgment (often presented as a tendency to interpret non-threatening stimuli as threatening), and dysfunctional decision processing.
Compared to individuals with a normal number of chromosomes, males affected by Klinefelter's syndrome may display behavioral abnormalities. These are phenotypically displayed as higher level of anxiety and depression, and mood dysregulation. These neurocognitive abnormalities are most likely due to the presence of the extra X chromosome, as indicated by studies carried out on animal models carrying an extra X chromosome.
Cause
Klinefelter syndrome is not an inherited condition. Maternal age is the only known risk factor.[ Women at 40 years have a four times higher risk for a child with Klinefelter syndrome than women aged 24 years.]
The extra chromosome is retained because of a nondisjunction event during paternal meiosis I, maternal meiosis I, or maternal meiosis II (gametogenesis). The relevant nondisjunction in meiosis I occurs when homologous chromosomes, in this case the X and Y or two X sex chromosomes, fail to separate, producing a sperm with an X and a Y chromosome or an egg with two X chromosomes. Fertilizing a normal (X) egg with this sperm produces an XXY offspring (Klinefelter). Fertilizing a double X egg with a normal sperm also produces an XXY offspring (Klinefelter).
Another mechanism for retaining the extra chromosome is through a nondisjunction event during meiosis II in the egg. Nondisjunction occurs when sister chromatids on the sex chromosome, in this case an X and an X, fail to separate. An XX egg is produced, which when fertilized with a Y sperm, yields an XXY offspring. This XXY chromosome arrangement is one of the most common genetic variations from the XY karyotype, occurring in about one in 500 live male births.[ See also Triple X syndrome.
In mammals with more than one X chromosome, the ]gene
In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
s on all but one X chromosome are not expressed; this is known as X inactivation. This happens in XXY males, as well as normal XX females. However, in XXY males, a few genes located in the pseudoautosomal regions of their X chromosomes have corresponding genes on their Y chromosome and are capable of being expressed.
Variations
The condition 48, XXYY or 48,XXXY occurs in one in 18,000–50,000 male births. The incidence of 49,XXXXY is one in 85,000 to 100,000 male births. These variations are extremely rare. Additional chromosomal material can contribute to cardiac, neurological, orthopedic, and other anomalies.
About 15–20% of males with KS may have a mosaic
A mosaic is a pattern or image made of small regular or irregular pieces of colored stone, glass or ceramic, held in place by plaster/mortar, and covering a surface. Mosaics are often used as floor and wall decoration, and were particularly pop ...
47,XXY/46,XY constitutional karyotype and varying degrees of spermatogenic failure. Often, symptoms are milder in mosaic cases, with regular male secondary sex characteristics and testicular volume even falling within typical adult ranges. Another possible mosaicism is 47,XXY/46,XX with clinical features suggestive of KS and male phenotype, but this is very rare. Thus far, only about 10 cases of 47,XXY/46,XX have been described in literature.
Analogous XXY syndromes are known to occur in cat
The cat (''Felis catus'') is a domestic species of small carnivorous mammal. It is the only domesticated species in the family Felidae and is commonly referred to as the domestic cat or house cat to distinguish it from the wild members of ...
s—specifically, the presence of calico
Calico (; in British usage since 1505) is a heavy plain-woven textile made from unbleached, and often not fully processed, cotton. It may also contain unseparated husk parts. The fabric is far coarser than muslin, but less coarse and thick than ...
or tortoiseshell
Tortoiseshell or tortoise shell is a material produced from the shells of the larger species of tortoise and turtle, mainly the hawksbill sea turtle, which is a critically endangered species according to the IUCN Red List largely because of it ...
markings in male cats is an indicator of the relevant abnormal karyotype. As such, male cats with calico or tortoiseshell markings are a model organism for KS, because a color gene involved in cat tabby coloration is on the X chromosome.
Random X-inactivation
Women typically have two X chromosomes, with half of their X chromosomes switching off early in embryonic development. The same happens with people with Klinefelter's, including in both cases a small proportion of individuals with a skewed ratio between the two Xs.
Diagnosis
The standard diagnostic method is the analysis of the chromosomes' karyotype on lymphocyte
A lymphocyte is a type of white blood cell (leukocyte) in the immune system of most vertebrates. Lymphocytes include natural killer cells (which function in cell-mediated, cytotoxic innate immunity), T cells (for cell-mediated, cytotoxic ad ...
s. A small blood sample is sufficient as test material. In the past, the observation of the Barr body was common practice, as well. To investigate the presence of a possible mosaicism, analysis of the karyotype using cells from the oral mucosa is performed. Physical characteristics of a Klinefelter syndrome can be tall stature, low body hair, and occasionally an enlargement of the breast. Usually, a small testicle volume of 1–5 ml per testicle (standard values: 12–30 ml) occurs. During puberty and adulthood, low testosterone levels with increased levels of the pituitary hormones FSH and LH in the blood can indicate the presence of Klinefelter syndrome. A spermiogram
A semen analysis (plural: semen analyses), also called seminogram or spermiogram, evaluates certain characteristics of a male's semen and the sperm contained therein. It is done to help evaluate male fertility, whether for those seeking pregnancy ...
can also be part of the further investigation. Often. an azoospermia is present, or rarely an oligospermia.[ Furthermore, Klinefelter syndrome can be diagnosed as a coincidental prenatal finding in the context of invasive prenatal diagnosis (amniocentesis, chorionic villus sampling). About 10% of KS cases are found by prenatal diagnosis.
The symptoms of KS are often variable, so a karyotype analysis should be ordered when small testes, infertility, gynecomastia, long arms/legs, developmental delay, speech/language deficits, learning disabilities/academic issues, and/or behavioral issues are present in an individual.]
Treatment
As the genetic variation is irreversible, no causal therapy is available. From the onset of puberty, the existing testosterone deficiency can be compensated by appropriate hormone-replacement therapy. Testosterone preparations are available in the form of syringes, patches, or gel. If gynecomastia is present, the surgical removal of the breast may be considered for both the psychological reasons and to reduce the risk of breast cancer.
The use of behavioral therapy can mitigate any language disorders, difficulties at school, and socialization. An approach by occupational therapy
Occupational therapy (OT) is a global healthcare profession. It involves the use of assessment and intervention to develop, recover, or maintain the meaningful activities, or ''occupations'', of individuals, groups, or communities. The field o ...
is useful in children, especially those who have dyspraxia.
Infertility treatment
Methods of reproductive medicine, such as intracytoplasmic sperm injection (ICSI) with previously conducted testicular sperm extraction (TESE), have led to men with Klinefelter syndrome producing biological offspring. By 2010, over 100 successful pregnancies have been reported using IVF technology with surgically removed sperm material from males with KS.
Prognosis
The lifespan of individuals with Klinefelter syndrome appears to be reduced by around 2.1 years compared to the general male population. These results are still questioned data, are not absolute, and need further testing.
Epidemiology
This syndrome, evenly distributed in all ethnic groups
An ethnic group or an ethnicity is a grouping of people who identify with each other on the basis of shared attributes that distinguish them from other groups. Those attributes can include common sets of traditions, ancestry, language, history ...
, has a prevalence
In epidemiology, prevalence is the proportion of a particular population found to be affected by a medical condition (typically a disease or a risk factor such as smoking or seatbelt use) at a specific time. It is derived by comparing the number o ...
of approximately four subjects per every 10,000 (0.04%) males in the general population. However, it is estimated that only 25% of the individuals with Klinefelter syndrome are diagnosed throughout their lives. The rate of Klinefelter syndrome among infertile males is 3.1%. The syndrome is also the main cause of male hypogonadism.
History
The syndrome was named after American endocrinologist Harry Klinefelter, who in 1942 worked with Fuller Albright and E. C. Reifenstein at Massachusetts General Hospital
Massachusetts General Hospital (Mass General or MGH) is the original and largest teaching hospital of Harvard Medical School located in the West End neighborhood of Boston, Massachusetts. It is the third oldest general hospital in the United State ...
in Boston, Massachusetts, and first described it in the same year. The account given by Klinefelter came to be known as Klinefelter syndrome as his name appeared first on the published paper, and seminiferous tubule dysgenesis was no longer used. Considering the names of all three researchers, it is sometimes also called Klinefelter–Reifenstein–Albright syndrome.The Klinefelter-Reifenstein-Albright syndrome.
on biomedsearch.com, retrieved 26 August 2017 In 1956, Klinefelter syndrome was found to result from an extra chromosome. Plunkett and Barr found the sex chromatin body in cell nuclei of the body. This was further clarified as XXY in 1959 by Patricia Jacobs and John Anderson Strong.[
] The first published report of a man with a 47,XXY karyotype was by Patricia Jacobs and John Strong at Western General Hospital in Edinburgh, Scotland
Edinburgh ( ; gd, Dùn Èideann ) is the capital city of Scotland and one of its 32 council areas. Historically part of the county of Midlothian (interchangeably Edinburghshire before 1921), it is located in Lothian on the southern shore of t ...
, in 1959. This karyotype was found in a 24-year-old man who had signs of KS. Jacobs described her discovery of this first reported human or mammalian chromosome aneuploidy
Aneuploidy is the presence of an abnormal number of chromosomes in a cell, for example a human cell having 45 or 47 chromosomes instead of the usual 46. It does not include a difference of one or more complete sets of chromosomes. A cell with a ...
in her 1981 William Allan Memorial Award address.
In August 2022, a team of scientists published a study of a skeleton found at Torre Velha, Municipality of Bragança in north-eastern Portugal
Portugal, officially the Portuguese Republic, In recognized minority languages of Portugal:
:* mwl, República Pertuesa is a country located on the Iberian Peninsula, in Southwestern Europe, and whose territory also includes the Macaronesian ...
. The male was buried in a cut grave around 1,000CE, and found from DNA tests to be the earliest known person with this syndrome.[A 1000-year-old case of Klinefelter's syndrome diagnosed by integrating morphology, osteology, and genetics](_blank)
Xavier Roca-Rada et al, The Lancet
''The Lancet'' is a weekly peer-reviewed general medical journal and one of the oldest of its kind. It is also the world's highest-impact academic journal. It was founded in England in 1823.
The journal publishes original research articles, ...
, Volume 400, Issue 10353, 27 August 2022 – 2 September 2022, Pages 691-692
See also
* Aneuploidy
Aneuploidy is the presence of an abnormal number of chromosomes in a cell, for example a human cell having 45 or 47 chromosomes instead of the usual 46. It does not include a difference of one or more complete sets of chromosomes. A cell with a ...
* Intersex
Intersex people are individuals born with any of several sex characteristics including chromosome patterns, gonads, or genitals that, according to the Office of the United Nations High Commissioner for Human Rights, "do not fit typical b ...
* Turner syndrome
Turner syndrome (TS), also known as 45,X, or 45,X0, is a genetic condition in which a female is partially or completely missing an X chromosome. Signs and symptoms vary among those affected. Often, a short and webbed neck, low-set ears, low h ...
* XYY syndrome
XYY syndrome, also known as Jacobs syndrome, is an aneuploid genetic condition in which a male has an extra Y chromosome. There are usually few symptoms. These may include being taller than average, acne, and an increased risk of learning dis ...
* XXYY syndrome
* Taurodontism
* Trisomy X
Trisomy X, also known as triple X syndrome and characterized by the karyotype 47,XXX, is a chromosome disorder in which a female has an extra copy of the X chromosome. It is relatively common and occurs in 1 in 1,000 women but it is rarely diag ...
References
Further reading
*
External links
*
{{Authority control
Sex chromosome aneuploidies
Genetic anomalies
Wikipedia medicine articles ready to translate
Intersex variations
Chromosomal abnormalities