Klinefelter syndrome

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Klinefelter syndrome
Other namesXXY syndrome, Klinefelter's syndrome, Klinefelter-Reifenstein-Albright syndrome
Human chromosomesXXY01.png
47,XXY karyotype
Pronunciation
Specialty Medical genetics
Symptoms Varied; include above average height, weaker muscles, poor coordination, less body hair, breast growth, small testicle size, less interest in sex, infertility [1]
Complications Infertility, intellectual disability, [2] autoimmune disorders, breast cancer, venous thromboembolic disease, osteoporosis
Usual onsetAt fertilisation [3]
DurationLifelong
Causes Nondisjunction during gametogenesis or in a zygote [4]
Risk factors Older age of mother [5]
Diagnostic method Genetic testing (karyotype) [6]
PreventionNone
Treatment Physical therapy, speech and language therapy, Testosterone Supplementation, counseling [7]
Prognosis Nearly normal life expectancy [8]
Frequency1 in 500–1000 [5] [9]
Named after Harry Klinefelter

Klinefelter syndrome (KS), also known as 47,XXY, is a chromosome anomaly where a male has an extra X chromosome. [10] These complications commonly include infertility and small, poorly functioning testicles (if present). These symptoms are often noticed only at puberty, although this is one of the most common chromosomal disorders, occurring in one to two per 1,000 live births. It is named after American endocrinologist Harry Klinefelter, who identified the condition in the 1940s, along with his colleagues at Massachusetts General Hospital. [4] [5] [11] [12]

Contents

The syndrome is defined by the presence of at least one extra X chromosome in addition to a Y chromosome, yielding a total of 47 or more chromosomes rather than the usual 46. 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 diagnosed by the genetic test known as karyotyping. [4] [6] [13] [14]

Signs and symptoms

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Bodymorphproj mkg modA001 20070325 pos04.jpg
A person with typical untreated Klinefelter 46,XY/47,XXY mosaic, diagnosed at age 19 – a scar from biopsy is on his right breast above the nipple.

Klinefelter syndrome has different manifestations and these will vary from one patient to another. Among the primary features are infertility and small, poorly functioning testicles. Often, symptoms may be subtle and many people do not realize they are affected. In other cases, symptoms are more prominent and may include weaker muscles, greater height, poor motor coordination, less body hair, gynecomastia (breast growth), and low libido. In the majority of the cases, these symptoms are noticed only at puberty. [4] [6] [15]

Prenatal

Chromosomal abnormalities, including Klinefelter syndrome, are the most common cause of spontaneous abortion. [16] Generally, the severity of the malformations is proportional to the number of extra X chromosomes present in the karyotype. For example, patients with 49 chromosomes (XXXXY) have a lower IQ and more severe physical manifestations than those with 48 chromosomes (XXXY). [17]

Physical manifestations

As babies and children, those with XXY chromosomes may have lower muscle tone and reduced strength. They may sit up, crawl, and walk later than other infants. An average KS child will start walking at 19 months of age. They may also have less muscle control and coordination than other children of their age. [18]

During puberty, KS subjects show less muscular body, less facial and body hair, and broader hips as a consequence of low levels of testosterone. Delays in motor development may occur, which can be addressed through occupational and physical therapies. As teens, males with XXY may develop breast tissue, have weaker bones, and a lower energy level than others. Testicles are affected and are usually less than 2 cm in length (and always shorter than 3.5 cm), 1 cm in width, and 4ml in volume. Those with XXY chromosomes may also have microorchidism (i.e., small testicles). [18] [19]

By adulthood, individuals with KS tend to become taller than average, with proportionally longer arms and legs, less-muscular bodies, more belly fat, wider hips, narrower shoulders. Some will show little to no symptomology, a lanky, youthful build and facial appearance, or a rounded body type. Gynecomastia (increased breast tissue) in males is common, affecting up to 80% of cases. [20] Approximately 10% of males with XXY chromosomes have gynecomastia noticeable enough that they may choose to have surgery.[ citation needed ]

Individuals with KS are often infertile or have reduced fertility. Advanced reproductive assistance is sometimes possible in order to produce an offspring since approximately 50% of males with Klinefelter syndrome can produce sperm. [11] [21]

Psychological characteristics

Cognitive development

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 overcome through early intervention. 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. [22] [23]

The overall IQ tends to be lower than average. Language milestones may also be delayed, particularly when compared to other people their age. Between 25% and 85% of males with XXY have some kind of language problem, such as delay in learning to speak, trouble using language to express thoughts and needs, problems reading, and trouble processing what they hear. They may also have a harder time doing work that involves reading and writing, but most hold jobs and have successful careers. [18] [24]

Behavior and personality traits

Compared to individuals with a normal number of chromosomes, males affected by Klinefelter syndrome may display behavioral differences. These are phenotypically displayed as higher levels of anxiety and depression, mood dysregulation, impaired social skills, emotional immaturity during childhood, and low frustration tolerance. [25] [26] [27] These neurocognitive disabilities 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. [28]

In 1995, a scientific study evaluated the psychosocial adaptation of 39 adolescents with sex chromosome abnormalities. It demonstrated that males with XXY tend to be quiet, shy and undemanding; they are less self-confident, less active, and more helpful and obedient than other children their age. They may struggle in school and sports, meaning they may have more trouble "fitting in" with other kids. [24] [29]

As adults, they live lives similar to others without the condition; they have friends, families, and normal social relationships. Nonetheless, some individuals may experience social and emotional problems due to problems in childhood. They show a lower sex drive and low self-esteem, in most cases due to their feminine physical characteristics. [4] [24]

Concomitant illness

Those with XXY are more likely than others to have certain health problems, such as autoimmune disorders, breast cancer, venous thromboembolic disease, and osteoporosis. Nonetheless, the risk of breast cancer is still below the normal risk for women. These patients are also more prone to develop cardiovascular disease due to the predominance of metabolic abnormalities such as dyslipidemia and type 2 diabetes. It has not been demonstrated that hypertension is related with KS. [30] [31] [32]

In contrast to these potentially increased risks, rare X-linked recessive conditions are thought to occur less frequently in those with XXY than in those without, 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. [33]

Cause

Birth of a cell with karyotype XXY due to a nondisjunction event of one X chromosome from a Y chromosome during meiosis I in the male XXY syndrome M.svg
Birth of a cell with karyotype XXY due to a nondisjunction event of one X chromosome from a Y chromosome during meiosis I in the male
Birth of a cell with karyotype XXY due to a nondisjunction event of one X chromosome during meiosis II in the female XXY syndrome.svg
Birth of a cell with karyotype XXY due to a nondisjunction event of one X chromosome during meiosis II in the female

Klinefelter syndrome is not an inherited condition. The extra X chromosome comes from the mother in approximately 50% of the cases. Maternal age is the only known risk factor. Women at 40 years have a four-times-higher risk of a child with Klinefelter syndrome than women aged 24 years. [14] [34] [35]

The extra chromosome is retained because of a nondisjunction event during paternal meiosis I, maternal meiosis I, or maternal meiosis II, also known as 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 or Klinefelter offspring. Fertilizing a double X egg with a normal sperm also produces an XXY or Klinefelter offspring. [34] [36]

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 approximately one in 500 live male births. [4] [13] [36]

In mammals with more than one X chromosome, the genes 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. [37] [38]

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. [39] These variations are extremely rare. Additional chromosomal material can contribute to cardiac, neurological, orthopedic, urinogenital and other anomalies.[ citation needed ] Thirteen cases of individuals with a 47,XXY karyotype and a female phenotype have been described. [40]

Mosaicism

Approximately 15–20% [41] of males with KS may have a mosaic 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. [41] 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 approximately 10 cases of 47,XXY/46,XX have been described in literature. [42]

Random versus skewed 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. [43]

Pathogenesis

The term "hypogonadism" 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 level, but high serum follicle-stimulating hormone and luteinizing hormone levels, hypergonadotropic hypogonadism. [44] Despite this misunderstanding of the term, testicular growth is arrested. [44]

Destruction and hyalinization of the seminiferous tubules cause a reduction in the function of Sertoli cells and Leydig cells, leading to decreased production of FSH and testosterone. This results in impaired spermatogenesis and further endocrine dysfunction. [45]

Diagnosis

The standard diagnostic method is the analysis of the chromosomes' karyotype on lymphocytes. A small blood sample is sufficient as test material. In the past, the observation of the Barr body was common practice, as well. [46] 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. [32] 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 can also be part of the further investigation. Often, an azoospermia is present, or rarely an oligospermia. [14] Furthermore, Klinefelter syndrome can be diagnosed as a coincidental prenatal finding in the context of invasive prenatal diagnosis (amniocentesis, chorionic villus sampling). Approximately 10% of KS cases are found by prenatal diagnosis. [47]

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. [4]

Prognosis

The lifespan of individuals with Klinefelter syndrome appears to be reduced by around 2.1 years compared to the general male population. [48] These results are still questioned data, are not absolute, and need further testing. [49]

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. [50] 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 psychological benefits and to reduce the risk of breast cancer. [51] [52]

The use of behavioral therapy can mitigate any language disorders, difficulties at school, and socialization. An approach by occupational therapy is useful in children, especially those who have dyspraxia. [53]

Infertility treatment

Intracytoplasmic sperm injection Icsi.JPG
Intracytoplasmic sperm injection

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. [54] By 2010, over 100 successful pregnancies have been reported using in vitro fertilization technology with surgically removed sperm material from men with KS. [55]

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 in Boston, Massachusetts, and first described it in the same year. [11] [56] 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. [57] In 1956, Klinefelter syndrome was found to result from an extra chromosome. [58] 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. [59] 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, in 1959. [59] 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 in her 1981 William Allan Memorial Award address. [60]

Klinefelter syndrome has been identified in ancient burials. In August 2022, a team of scientists published a study of a skeleton found in Bragança, north-eastern Portugal, of a man who died around 1000 AD and was discovered by their investigations to have a 47,XXY karyotype. [61] In 2021, bioarchaeological investigation of the individual buried with the Suontaka sword, previously assumed to be a woman, concluded that person "whose gender identity may well have been non-binary", had Klinefelter syndrome. [62]

Cultural and social impacts

In many societies, the symptoms of Klinefelter syndrome have contributed to significant social stigma, particularly due to infertility and gynecomastia. Historically, these traits were often associated with a perceived lack of masculinity, which could result in social ostracism.[ citation needed ] However, in recent years, increased awareness and advocacy have led to a reduction in stigma, with individuals diagnosed with KS more likely to receive proper medical care and support. Advocacy organizations, such as the American Association for Klinefelter Syndrome Information and Support (AAKSIS), have played a crucial role in promoting understanding and improving the quality of life for affected individuals. [63]

Epidemiology

This syndrome, evenly distributed in all ethnic groups, has a prevalence of approximately four subjects per every 10,000 (0.04%) males in the general population. [35] [64] [65] [66] However, it is estimated that only 25% of the individuals with Klinefelter syndrome are diagnosed throughout their lives. [50] The rate of Klinefelter syndrome among infertile males is 3.1%. The syndrome is the main cause of male hypogonadism. [67] One survey in the United Kingdom found that the majority of people with KS identify as male, however, a significant number have a different gender identity. [68] The prevalence of KS is higher than expected in transgender women. [69]

See also

Related Research Articles

<span class="mw-page-title-main">XYY syndrome</span> Genetic condition in which a male has an extra Y chromosome

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 and an increased risk of learning disabilities. The person is generally otherwise normal, including typical rates of fertility.

<span class="mw-page-title-main">Turner syndrome</span> X chromosome monosomy

Turner syndrome (TS), commonly known as 45,X, or 45,X0, is a chromosomal disorder in which cells have only one X chromosome or are partially missing an X chromosome leading to the complete or partial deletion of the pseudoautosomal regions in the affected X chromosome. Most people have two sex chromosomes. The chromosomal abnormality is often present in just some cells, in which case it is known as Turner syndrome with mosaicism. 45,X0 with mosaicism can occur in males or females, but Turner syndrome without mosaicism only occurs in females. Signs and symptoms vary among those affected. Often, additional skin folds on the neck, arched palate, low-set ears, low hairline at the nape of the neck, shorter height, and lymphedema of the hands and feet. Typically, those affected do not develop menstrual periods or mammary glands without hormone treatment and are unable to reproduce without assistive reproductive technology. Small chin(micrognathia),loose folds of skin on the neck, slanted eyes, and prominent ears are found in Turner syndrome, though not all will show it. Heart defects, Type II diabetes, and hypothyroidism occur in the disorder more frequently than average. Most people with Turner syndrome have normal intelligence; however, many have problems with spatial visualization that may be needed in order to learn mathematics. Ptosis and conductive hearing loss also occur more often than average.

Hypogonadism means diminished functional activity of the gonads—the testicles or the ovaries—that may result in diminished production of sex hormones. Low androgen levels are referred to as hypoandrogenism and low estrogen as hypoestrogenism. These are responsible for the observed signs and symptoms in both males and females.

Kallmann syndrome (KS) is a genetic disorder that prevents a person from starting or fully completing puberty. Kallmann syndrome is a form of a group of conditions termed hypogonadotropic hypogonadism. To distinguish it from other forms of hypogonadotropic hypogonadism, Kallmann syndrome has the additional symptom of a total lack of sense of smell (anosmia) or a reduced sense of smell. If left untreated, people will have poorly defined secondary sexual characteristics, show signs of hypogonadism, almost invariably are infertile and are at increased risk of developing osteoporosis. A range of other physical symptoms affecting the face, hands and skeletal system can also occur.

<span class="mw-page-title-main">XX male syndrome</span> Congenital condition where an individual with a 46,XX karyotype is male

XX male syndrome, also known as de la Chapelle syndrome, is a rare intersex condition in which an individual with a 46,XX karyotype develops a male phenotype. Synonyms for XX male syndrome include 46,XX testicular difference of sex development

<span class="mw-page-title-main">XXYY syndrome</span> Extra X and Y chromosome in males

XXYY syndrome is a sex chromosome anomaly in which males have two extra chromosomes, one X and one Y chromosome. Human cells usually contain two sex chromosomes, one from the mother and one from the father. Usually, females have two X chromosomes (XX) and males have one X and one Y chromosome (XY). The appearance of at least one Y chromosome with a properly functioning SRY gene makes a male. Therefore, humans with XXYY are genotypically male. Males with XXYY syndrome have 48 chromosomes instead of the typical 46. This is why XXYY syndrome is sometimes written as 48, XXYY syndrome or 48, XXYY. It affects an estimated one in every 18,000–40,000 male births.

<span class="mw-page-title-main">XXXXY syndrome</span> Chromosomal anomaly

49,XXXXY syndrome is an extremely rare aneuploidic sex chromosomal abnormality. It occurs in approximately 1 out of 85,000 to 100,000 males. This syndrome is the result of maternal non-disjunction during both meiosis I and II. It was first diagnosed in 1960 and was coined Fraccaro syndrome after the researcher.

<span class="mw-page-title-main">Disorders of sex development</span> Medical conditions involving the development of the reproductive system

Disorders of sex development (DSDs), also known as differences in sex development or variations in sex characteristics (VSC), are congenital conditions affecting the reproductive system, in which development of chromosomal, gonadal, or anatomical sex is atypical. DSDs is a clinical term used in some medical settings for what are otherwise referred to as intersex traits. The term was first introduced in 2006 and has not been without controversy.

Wilson-Turner syndrome (WTS), also known as mental retardation X linked syndromic 6 (MRXS6), and mental retardation X linked with gynecomastia and obesity is a congenital condition characterized by intellectual disability and associated with childhood-onset obesity. It is found to be linked to the X chromosome and caused by a mutation in the HDAC8 gene, which is located on the q arm at locus 13.1. Individuals with Wilson–Turner syndrome have a spectrum of physical characteristics including dysmorphic facial features, hypogonadism, and short stature. Females generally have milder phenotypes than males. This disorder affects all demographics equally and is seen in less than one in one million people.

Harry Fitch Klinefelter Jr. was an American rheumatologist and endocrinologist. Klinefelter syndrome is named after him.

46,XX/46,XY is either a chimeric or mosaic genetic condition characterized by the presence of some cells that express a 46,XX karyotype and some cells that express a 46,XY karyotype in a single human being. While some individuals with this condition may be classified as intersex, others may have typical male or female characteristics.

Hypergonadotropic hypogonadism (HH), also known as primary or peripheral/gonadal hypogonadism or primary gonadal failure, is a condition which is characterized by hypogonadism which is due to an impaired response of the gonads to the gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH), and in turn a lack of sex steroid production. As compensation and the lack of negative feedback, gonadotropin levels are elevated. Individuals with HH have an intact and functioning hypothalamus and pituitary glands so they are still able to produce FSH and LH. HH may present as either congenital or acquired, but the majority of cases are of the former nature. HH can be treated with hormone replacement therapy.

XXXYsyndrome is a genetic condition characterized by a sex chromosome aneuploidy, where individuals have two extra X chromosomes. People in most cases have two sex chromosomes: an X and a Y or two X chromosomes. The presence of one Y chromosome with a functioning SRY gene causes the expression of genes that determine maleness. Because of this, XXXY syndrome only affects males. The additional two X chromosomes in males with XXXY syndrome causes them to have 48 chromosomes, instead of the typical 46. XXXY syndrome is therefore often referred to as 48,XXXY. There is a wide variety of symptoms associated with this syndrome, including cognitive and behavioral problems, taurodontism, and infertility. This syndrome is usually inherited via a new mutation in one of the parents' gametes, as those affected by it are usually infertile. It is estimated that XXXY affects one in every 50,000 male births.

45,X/46,XY mosaicism, also known as X0/XY mosaicism and mixed gonadal dysgenesis, is a mutation of sex development in humans associated with sex chromosome aneuploidy and mosaicism of the Y chromosome. It is a fairly rare chromosomal disorder at birth, with an estimated incidence rate of about 1 in 15,000 live births. Mosaic loss of the Y chromosome in previously non-mosaic men grows increasingly common with age.

<span class="mw-page-title-main">XYYY syndrome</span> Chromosomal disorder

XYYY syndrome, also known as 48,XYYY, is a chromosomal disorder in which a male has two extra copies of the Y chromosome. The syndrome is exceptionally rare, with only twelve recorded cases. The presentation of the syndrome is heterogeneous, but appears to be more severe than its counterpart XYY syndrome. Common traits include borderline to mild intellectual disability, infertility, radioulnar synostosis, and in some cases tall stature.

<span class="mw-page-title-main">Tetrasomy X</span> Chromosomal disorder with 4 X chromosomes

Tetrasomy X, also known as 48,XXXX, is a chromosomal disorder in which a female has four, rather than two, copies of the X chromosome. It is associated with intellectual disability of varying severity, characteristic "coarse" facial features, heart defects, and skeletal anomalies such as increased height, clinodactyly, and radioulnar synostosis. Tetrasomy X is a rare condition, with few medically recognized cases; it is estimated to occur in approximately 1 in 50,000 females.

Sexual anomalies, also known as sexual abnormalities, are a set of clinical conditions due to chromosomal, gonadal and/or genitalia variation. Individuals with congenital (inborn) discrepancy between sex chromosome, gonadal, and their internal and external genitalia are categorised as individuals with a disorder of sex development (DSD). Afterwards, if the family or individual wishes, they can partake in different management and treatment options for their conditions.

<span class="mw-page-title-main">Pentasomy X</span> Chromosomal disorder

Pentasomy X, also known as 49,XXXXX, is a chromosomal disorder in which a female has five, rather than two, copies of the X chromosome. Pentasomy X is associated with short stature, intellectual disability, characteristic facial features, heart defects, skeletal anomalies, and pubertal and reproductive abnormalities. The condition is exceptionally rare, with an estimated prevalence between 1 in 85,000 and 1 in 250,000.

<span class="mw-page-title-main">Trisomy X</span> Chromosome disorder in women

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 females, but is rarely diagnosed; fewer than 10% of those with the condition know they have it.

<span class="mw-page-title-main">XXXYY syndrome</span> Chromosomal disorder

XXXYY syndrome, also known as 49,XXXYY, is a chromosomal disorder in which a male has three copies of the X chromosome and two copies of the Y chromosome. XXXYY syndrome is exceptionally rare, with only eight recorded cases. Little is known about its presentation, but associated characteristics include intellectual disability, anomalies of the external genitalia, and characteristic physical and facial features. It is not caused by characteristics of the parents, but rather occurs via nondisjunction, a random event in gamete development. The karyotype observed in the syndrome is formally known as 49,XXXYY, which represents the 49 chromosomes observed in the disorder as compared to the 46 in normal human development.

References

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  12. ↑ Visootsak, Jeannie; Graham, John M (2006-10-24). "Klinefelter syndrome and other sex chromosomal aneuploidies". Orphanet Journal of Rare Diseases. 1 (1): 42. doi: 10.1186/1750-1172-1-42 . ISSN   1750-1172. PMC   1634840 . PMID   17062147.
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