Klinefelter's syndrome
Encyclopedia
Klinefelter syndrome, 46/47, XXY, or XXY syndrome is a condition in which human males have an extra X chromosome. While females have an XX chromosomal makeup, and males an XY, affected individuals have at least two X chromosome
s and at least one Y chromosome
. Because of the extra chromosome
, individuals with the condition are usually referred to as "XXY Males", or "47, XXY Males".
In humans, Klinefelter syndrome is the most common sex chromosome disorder in males and the second most common condition caused by the presence of extra chromosomes. The condition exists in roughly 1 out of every 500-650 males but many of these people may not show symptoms. Other mammals also have the XXY syndrome, including mice.
Principal effects include hypogonadism
and reduced fertility
. A variety of other physical and behavioural differences and problems are common, though severity varies and many boys and men with the condition have few detectable symptoms.
The syndrome was named after Dr. Harry Klinefelter
, who in 1942 worked with Fuller Albright at Massachusetts General Hospital
in Boston, Massachusetts and first described it in the same year.
, or may have reduced fertility. Advanced reproductive assistance is sometimes possible. Some degree of language learning or reading impairment may be present, and neuropsychological testing often reveals deficits in executive functions
, although these deficits can often be successfully ameliorated through early intervention. There may also be delays in motor development which can be addressed through occupational therapy. In adults, possible characteristics vary widely and include little to no signs of affectedness, a lanky, youthful build and facial appearance, or a rounded body type with some degree of gynecomastia
(increased breast tissue). Gynecomastia is present to some extent 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.
The term hypogonadism
in XXY symptoms is often misinterpreted to mean "small testicles" or "small penis". In fact, it means decreased testicular hormone/endocrine function. Because of this (primary) hypogonadism, individuals will often have a low serum testosterone
level but high serum follicle-stimulating hormone
(FSH) and luteinizing hormone
(LH) levels. Despite this misunderstanding of the term, however, it is true that XXY men may also have microorchidism
(i.e. small testicles).
The more severe end of the spectrum
of symptom expression is also associated with an increased risk of germ cell tumor
s, male breast cancer
, and osteoporosis
, risks shared to varying degrees with females.
In contrast to these potentially increased risks, it is currently thought that rare X-linked recessive conditions occur less frequently in XXY males than in normal 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.
There are many variances within the XXY population, just as in the most common 46,XY population. While it is possible to characterise 47,XXY males with certain body types, that in itself should not be the method of identification as to whether or not someone has 47,XXY. The only reliable method of identification is karyotype
testing.
is used to confirm the diagnosis. In this procedure, a small blood sample is drawn. White blood cell
s are then separated from the sample, mixed with tissue culture medium
, incubated, and checked for chromosomal abnormalities, such as an extra X chromosome.
Diagnosis can also be made prenatally via chorionic villus sampling
or amniocentesis
, tests in which fetal tissue is extracted and the fetal DNA
is examined for genetic abnormalities. A 2002 literature review of elective abortion
rates found that approximately 58% of pregnancies in the United States with a diagnosis of Klinefelter syndrome were terminated.
event during meiosis I (gametogenesis). Nondisjunction occurs when homologous chromosomes, in the case the X and Y sex chromosomes, fail to separate, producing a sperm with an X and a Y chromosome. Fertilizing a normal (X) egg produces an XXY offspring.
The XXY chromosome arrangement is one of the most common genetic variations from the XY karyotype
, occurring in about 1 in 500 live male births.
Another mechanism for retaining the extra X chromosome is through a nondisjunction event during meiosis II in the female. Nondisjunction will occur 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 XXY offspring.
In mammal
s with more than one X chromosome, the gene
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 region
s of their X chromosomes, have corresponding genes on their Y chromosome and are capable of being expressed.
The first published report of a man with a 47,XXY karyotype was by Patricia A. Jacobs and Dr. J.A. Strong at Western General Hospital
in Edinburgh, Scotland in 1959. This karyotype was found in a 24-year-old man who had signs of Klinefelter syndrome. Dr. Jacobs described her discovery of this first reported human or mammalian chromosome aneuploidy
in her 1981 William Allan Memorial Award address.
is no longer generally considered a variation of KS, although it has not yet been assigned an ICD-10
code.
Males with Klinefelter syndrome may have a mosaic
47,XXY/46,XY constitutional karyotype
and varying degrees of spermatogenic failure. Mosaicism 47,XXY/46,XX with clinical features suggestive of Klinefelter syndrome is very rare. Thus far, only about 10 cases have been described in literature.
treatment is an option for some individuals who desire a more masculine appearance and identity. Often individuals that have noticeable breast tissue or hypogonadism
experience depression and/or social anxiety because they are outside of social norms. This is academically referred to as psychosocial
morbidity. At least one study indicates that planned and timed support should be provided for young men with Klinefelter syndrome to ameliorate current poor psychosocial outcomes.
By 2010 over 100 successful pregnancies have been reported using IVF technology with surgically removed sperm material from men with Klinefelter syndrome.
X chromosome
The X chromosome is one of the two sex-determining chromosomes in many animal species, including mammals and is common in both males and females. It is a part of the XY sex-determination system and X0 sex-determination system...
s and at least one Y chromosome
Y chromosome
The Y chromosome is one of the two sex-determining chromosomes in most mammals, including humans. In mammals, it contains the gene SRY, which triggers testis development if present. The human Y chromosome is composed of about 60 million base pairs...
. Because of the extra chromosome
Trisomy
A trisomy is a type of polysomy in which there are three copies, instead of the normal two, of a particular chromosome. A trisomy is a type of aneuploidy .-Description and causes:...
, individuals with the condition are usually referred to as "XXY Males", or "47, XXY Males".
In humans, Klinefelter syndrome is the most common sex chromosome disorder in males and the second most common condition caused by the presence of extra chromosomes. The condition exists in roughly 1 out of every 500-650 males but many of these people may not show symptoms. Other mammals also have the XXY syndrome, including mice.
Principal effects include hypogonadism
Hypogonadism
Hypogonadism is a medical term for decreased functional activity of the gonads. Low testosterone is caused by a decline or deficiency in gonadal production of testosterone in males...
and reduced fertility
Fertility
Fertility is the natural capability of producing offsprings. As a measure, "fertility rate" is the number of children born per couple, person or population. Fertility differs from fecundity, which is defined as the potential for reproduction...
. A variety of other physical and behavioural differences and problems are common, though severity varies and many boys and men with the condition have few detectable symptoms.
The syndrome was named after Dr. Harry Klinefelter
Harry Klinefelter
Harry Fitch Klinefelter, Jr. was an American rheumatologist and endocrinologist.-Biography:Klinefelter studied first at the University of Virginia, Charlottesville and then at Johns Hopkins Medical School. After his graduation in 1937 he continued his training in internal medicine at the Johns...
, who in 1942 worked with Fuller Albright at Massachusetts General Hospital
Massachusetts General Hospital
Massachusetts General Hospital is a teaching hospital and biomedical research facility in the West End neighborhood of Boston, Massachusetts...
in Boston, Massachusetts and first described it in the same year.
Signs and symptoms
Affected males are sometimes infertileInfertility
Infertility primarily refers to the biological inability of a person to contribute to conception. Infertility may also refer to the state of a woman who is unable to carry a pregnancy to full term...
, or may have reduced fertility. Advanced reproductive assistance is sometimes possible. Some degree of language learning or reading impairment may be present, and neuropsychological testing often reveals deficits in executive functions
Executive functions
The executive system is a theorized cognitive system in psychology that controls and manages other cognitive processes. It is responsible for processes that are sometimes referred to as the executive function, executive functions, supervisory attentional system, or cognitive control...
, although these deficits can often be successfully ameliorated through early intervention. There may also be delays in motor development which can be addressed through occupational therapy. In adults, possible characteristics vary widely and include little to no signs of affectedness, a lanky, youthful build and facial appearance, or a rounded body type with some degree of gynecomastia
Gynecomastia
Gynecomastia or Gynaecomastia, , is the abnormal development of large mammary glands in males resulting in breast enlargement. The term comes from the Greek γυνή gyné meaning "woman" and μαστός mastós meaning "breast"...
(increased breast tissue). Gynecomastia is present to some extent in about a third of affected individuals, a slightly higher percentage than in the XY population. About 10% of XXY males have gynecomastia
Gynecomastia
Gynecomastia or Gynaecomastia, , is the abnormal development of large mammary glands in males resulting in breast enlargement. The term comes from the Greek γυνή gyné meaning "woman" and μαστός mastós meaning "breast"...
noticeable enough that they may choose to have cosmetic surgery.
The term hypogonadism
Hypogonadism
Hypogonadism is a medical term for decreased functional activity of the gonads. Low testosterone is caused by a decline or deficiency in gonadal production of testosterone in males...
in XXY symptoms is often misinterpreted to mean "small testicles" or "small penis". In fact, it means decreased testicular hormone/endocrine function. Because of this (primary) hypogonadism, individuals will often have a low serum testosterone
Testosterone
Testosterone is a steroid hormone from the androgen group and is found in mammals, reptiles, birds, and other vertebrates. In mammals, testosterone is primarily secreted in the testes of males and the ovaries of females, although small amounts are also secreted by the adrenal glands...
level but high serum follicle-stimulating hormone
Follicle-stimulating hormone
Follicle-stimulating hormone is a hormone found in humans and other animals. It is synthesized and secreted by gonadotrophs of the anterior pituitary gland. FSH regulates the development, growth, pubertal maturation, and reproductive processes of the body. FSH and Luteinizing hormone act...
(FSH) and luteinizing hormone
Luteinizing hormone
Luteinizing hormone is a hormone produced by the anterior pituitary gland. In females, an acute rise of LH called the LH surge triggers ovulation and development of the corpus luteum. In males, where LH had also been called interstitial cell-stimulating hormone , it stimulates Leydig cell...
(LH) levels. Despite this misunderstanding of the term, however, it is true that XXY men may also have microorchidism
Microorchidism
Microorchidism is the medical term used to describe a genetic disorder found in males where a subject has abnormally small testes. The condition is associated with a number of other genetic disorders, including Klinefelter's Syndrome and Prader-Willi syndrome, as well as other multiple...
(i.e. small testicles).
The more severe end of the spectrum
Spectrum
A spectrum is a condition that is not limited to a specific set of values but can vary infinitely within a continuum. The word saw its first scientific use within the field of optics to describe the rainbow of colors in visible light when separated using a prism; it has since been applied by...
of symptom expression is also associated with an increased risk of germ cell tumor
Germ cell tumor
A germ cell tumor is a neoplasm derived from germ cells. Germ cell tumors can be cancerous or non-cancerous tumors. Germ cells normally occur inside the gonads...
s, male breast cancer
Male breast cancer
Male breast cancer is a relatively rare cancer in men that originates from the breast. As it presents a similar pathology as female breast cancer, assessment and treatment relies on experiences and guidelines that have been developed in female patients. The optimal treatment is currently not...
, and osteoporosis
Osteoporosis
Osteoporosis is a disease of bones that leads to an increased risk of fracture. In osteoporosis the bone mineral density is reduced, bone microarchitecture is deteriorating, and the amount and variety of proteins in bone is altered...
, risks shared to varying degrees with females.
In contrast to these potentially increased risks, it is currently thought that rare X-linked recessive conditions occur less frequently in XXY males than in normal XY males, since these conditions are transmitted by genes on the X chromosome, and people with two X chromosomes are typically only carriers
Genetic carrier
A genetic carrier , is a person or other organism that has inherited a genetic trait or mutation, but who does not display that trait or show symptoms of the disease. They are, however, able to pass the gene onto their offspring, who may then express the gene...
rather than affected by these X-linked recessive conditions.
There are many variances within the XXY population, just as in the most common 46,XY population. While it is possible to characterise 47,XXY males with certain body types, that in itself should not be the method of identification as to whether or not someone has 47,XXY. The only reliable method of identification is karyotype
Karyotype
A karyotype is the number and appearance of chromosomes in the nucleus of an eukaryotic cell. The term is also used for the complete set of chromosomes in a species, or an individual organism.p28...
testing.
Diagnosis
A karyotypeKaryotype
A karyotype is the number and appearance of chromosomes in the nucleus of an eukaryotic cell. The term is also used for the complete set of chromosomes in a species, or an individual organism.p28...
is used to confirm the diagnosis. In this procedure, a small blood sample is drawn. White blood cell
White blood cell
White blood cells, or leukocytes , are cells of the immune system involved in defending the body against both infectious disease and foreign materials. Five different and diverse types of leukocytes exist, but they are all produced and derived from a multipotent cell in the bone marrow known as a...
s are then separated from the sample, mixed with tissue culture medium
Growth medium
A growth medium or culture medium is a liquid or gel designed to support the growth of microorganisms or cells, or small plants like the moss Physcomitrella patens.There are different types of media for growing different types of cells....
, incubated, and checked for chromosomal abnormalities, such as an extra X chromosome.
Diagnosis can also be made prenatally via chorionic villus sampling
Chorionic villus sampling
Chorionic villus sampling , sometimes misspelled "chorionic villous sampling", is a form of prenatal diagnosis to determine chromosomal or genetic disorders in the fetus. It entails sampling of the chorionic villus and testing it...
or amniocentesis
Amniocentesis
Amniocentesis is a medical procedure used in prenatal diagnosis of chromosomal abnormalities and fetal infections, in which a small amount of amniotic fluid, which contains fetal tissues, is sampled from the amnion or amniotic sac surrounding a developing fetus, and the fetal DNA is examined for...
, tests in which fetal tissue is extracted and the fetal DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
is examined for genetic abnormalities. A 2002 literature review of elective abortion
Abortion
Abortion is defined as the termination of pregnancy by the removal or expulsion from the uterus of a fetus or embryo prior to viability. An abortion can occur spontaneously, in which case it is usually called a miscarriage, or it can be purposely induced...
rates found that approximately 58% of pregnancies in the United States with a diagnosis of Klinefelter syndrome were terminated.
Cause
The extra X chromosome is retained because of a nondisjunctionNondisjunction
Nondisjunction is the failure of chromosome pairs to separate properly during meiosis stage 1 or stage 2. This could arise from a failure of homologous chromosomes to separate in meiosis I, or the failure of sister chromatids to separate during meiosis II or mitosis. The result of this error is a...
event during meiosis I (gametogenesis). Nondisjunction occurs when homologous chromosomes, in the case the X and Y sex chromosomes, fail to separate, producing a sperm with an X and a Y chromosome. Fertilizing a normal (X) egg produces an XXY offspring.
The XXY chromosome arrangement is one of the most common genetic variations from the XY karyotype
Karyotype
A karyotype is the number and appearance of chromosomes in the nucleus of an eukaryotic cell. The term is also used for the complete set of chromosomes in a species, or an individual organism.p28...
, occurring in about 1 in 500 live male births.
Another mechanism for retaining the extra X chromosome is through a nondisjunction event during meiosis II in the female. Nondisjunction will occur 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 XXY offspring.
In mammal
Mammal
Mammals are members of a class of air-breathing vertebrate animals characterised by the possession of endothermy, hair, three middle ear bones, and mammary glands functional in mothers with young...
s with more than one X chromosome, the gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
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 region
Pseudoautosomal region
The pseudoautosomal regions, PAR1 and PAR2 are homologous sequences of nucleotides on the X and Y chromosomes.The pseudoautosomal regions get their name because any genes located within them are inherited just like any autosomal genes...
s of their X chromosomes, have corresponding genes on their Y chromosome and are capable of being expressed.
The first published report of a man with a 47,XXY karyotype was by Patricia A. Jacobs and Dr. J.A. Strong at Western General Hospital
Western General Hospital
The Western General Hospital , at Crewe Road, Edinburgh, Scotland is part of NHS Lothian, a Heath Board which provides a comprehensive range of adult and paediatric care to the people of Edinburgh, the Lothians and beyond.It is one of the main teaching hospitals affiliated to the University of...
in Edinburgh, Scotland in 1959. This karyotype was found in a 24-year-old man who had signs of Klinefelter syndrome. Dr. Jacobs described her discovery of this first reported human or mammalian chromosome aneuploidy
Aneuploidy
Aneuploidy is an abnormal number of chromosomes, and is a type of chromosome abnormality. An extra or missing chromosome is a common cause of genetic disorders . Some cancer cells also have abnormal numbers of chromosomes. Aneuploidy occurs during cell division when the chromosomes do not separate...
in her 1981 William Allan Memorial Award address.
Variations
The 48, XXYY (male) syndrome occurs in 1 in 18,000–40,000 births and has traditionally been considered to be a variation of Klinefelter syndrome. XXYY tetrasomyTetrasomy
A tetrasomy is a form of aneuploidy with the presence of four copies, instead of the normal two, of a particular chromosome.-Full:Full tetrasomy of an individual occurs due to non-disjunction when the cells are dividing to form egg and sperm cells . This can result in extra chromosomes in a sperm...
is no longer generally considered a variation of KS, although it has not yet been assigned an ICD-10
ICD-10
The International Statistical Classification of Diseases and Related Health Problems, 10th Revision is a medical classification list for the coding of diseases, signs and symptoms, abnormal findings, complaints, social circumstances, and external causes of injury or diseases, as maintained by the...
code.
Males with Klinefelter syndrome may have a mosaic
Mosaic (genetics)
In genetic medicine, a mosaic or mosaicism denotes the presence of two populations of cells with different genotypes in one individual who has developed from a single fertilized egg...
47,XXY/46,XY constitutional karyotype
Karyotype
A karyotype is the number and appearance of chromosomes in the nucleus of an eukaryotic cell. The term is also used for the complete set of chromosomes in a species, or an individual organism.p28...
and varying degrees of spermatogenic failure. Mosaicism 47,XXY/46,XX with clinical features suggestive of Klinefelter syndrome is very rare. Thus far, only about 10 cases have been described in literature.
Treatment
The genetic variation is irreversible. TestosteroneTestosterone
Testosterone is a steroid hormone from the androgen group and is found in mammals, reptiles, birds, and other vertebrates. In mammals, testosterone is primarily secreted in the testes of males and the ovaries of females, although small amounts are also secreted by the adrenal glands...
treatment is an option for some individuals who desire a more masculine appearance and identity. Often individuals that have noticeable breast tissue or hypogonadism
Hypogonadism
Hypogonadism is a medical term for decreased functional activity of the gonads. Low testosterone is caused by a decline or deficiency in gonadal production of testosterone in males...
experience depression and/or social anxiety because they are outside of social norms. This is academically referred to as psychosocial
Psychosocial
For a concept to be psychosocial means it relates to one's psychological development in, and interaction with, a social environment. The individual needs not be fully aware of this relationship with his or her environment. It was first commonly used by psychologist Erik Erikson in his stages of...
morbidity. At least one study indicates that planned and timed support should be provided for young men with Klinefelter syndrome to ameliorate current poor psychosocial outcomes.
By 2010 over 100 successful pregnancies have been reported using IVF technology with surgically removed sperm material from men with Klinefelter syndrome.
See also
- AneuploidyAneuploidyAneuploidy is an abnormal number of chromosomes, and is a type of chromosome abnormality. An extra or missing chromosome is a common cause of genetic disorders . Some cancer cells also have abnormal numbers of chromosomes. Aneuploidy occurs during cell division when the chromosomes do not separate...
- Intersexuality
- Mosaic (genetics)Mosaic (genetics)In genetic medicine, a mosaic or mosaicism denotes the presence of two populations of cells with different genotypes in one individual who has developed from a single fertilized egg...
- True hermaphroditismTrue hermaphroditismTrue hermaphroditism is a medical term for an intersex condition in which an individual is born with ovarian and testicular tissue.There may be an ovary on one side and a testis on the other, but more commonly one or both gonads is an ovotestis containing both types of tissue.It is rare—so...
- Turner SyndromeTurner syndromeTurner syndrome or Ullrich-Turner syndrome encompasses several conditions in human females, of which monosomy X is most common. It is a chromosomal abnormality in which all or part of one of the sex chromosomes is absent...
- XXYY syndrome