XYYY syndrome

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XYYY syndrome
Other names48,XYYY
Peripheral-blood-karyotype-result-belonging-to-the-subject-compatible-with-48-XYYY.png
Karyotype of XYYY syndrome
Specialty Medical genetics   OOjs UI icon edit-ltr-progressive.svg
Symptoms Infertility, behavioural issues, developmental delays
Usual onsetConception
DurationLifelong
Causes Aneuploidy
Diagnostic method Karyotype

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 (the fusion of the long bones in the forearm), and in some cases tall stature.

Contents

Presentation

The presentation of XYYY syndrome is variable and at this time not entirely clear. As all known cases were diagnosed postnatally (after birth), and the similar XYY syndrome is known to have a milder phenotype in prenatally than postnatally diagnosed cases, it is suspected that many cases of XYYY syndrome may be mild or asymptomatic. [1]

The intellectual abilities of known XYYY cases have varied, especially in cases with mosaicism, but in most cases are in the borderline intellectual functioning range (IQ between 70–85). [2] Performance IQ is often higher than verbal IQ. [3] Mild speech delays have been reported. [4] Basic self-care skills, such as toileting, dressing, eating, and hygiene, are normal or at most slightly delayed. [1] A number of minor skeletal anomalies are observed, such as clinodactyly, [5] radioulnar synostosis (the fusion of the long bones in the forearm), and poor dental development. These findings are also observed in other sex chromosome aneuploidies. [1] Height is normal to tall, with some cases of abnormally tall stature. [1] [5] Aside from severe acne in adolescence, XYYY syndrome is not associated with any obvious physical or facial abnormalities. [2]

Clinodactyly of the right hand Picture of right hand.jpg
Clinodactyly of the right hand

As very few cases of XYYY syndrome in adult men have been reported, drawing certain conclusions about sexual functioning and reproduction is difficult. However, low testosterone appears to be associated. All adult men with a non-mosaic 48,XYYY karyotype known to the medical literature have been azoospermic, though one man reported with a 46,XY/48,XYYY mosaic complement (81.1% 48,XYYY) had some evidence of spermatogenesis. [2] Some adults have had impulsive or aggressive sexual behaviour, while some have had low sex drives and no apparent sexual interest; one had gender dysphoria. [2] [6] Two men with XYYY syndrome are known to have had independent adult lives, marrying and finding employment, and only came to medical attention for infertility. [4] [7]

Behavioural issues, varying in severity, are associated with the syndrome. Some patients have been transferred to special schools, high-security group homes, or institutions due to severe aggression. [8] However, those cases with particularly severe behavioural issues have generally been from problematic or abusive familial backgrounds. [3] While some descriptions of the syndrome emphasize aggression as a characteristic, the majority of parent reports from a leading chromosome disorder charity emphasize insecurity, immaturity, and shyness. [1] Though teenage boys with XYYY syndrome may be at-risk adolescents, they are capable of positive identity formation, and case reports following the identity formation and personal development of XYYY adolescents have demonstrated a desire to have healthy relationships and integrate successfully into society. [8]

Causes

XYYY syndrome is caused by two extra copies of the Y chromosome, the chromosome that determines male sexual development. Sex chromosome aneuploidies are the most frequent form of aneuploidy in humans. [9] Though a 48-chromosome complement involving the autosomes would be unsurvivable, 48,XYYY and other high-level sex chromosome aneuploidies such as XXXY syndrome and tetrasomy X—or indeed 49-chromosome disorders such as pentasomy X—are survivable with relatively mild phenotypes due to the paucity of genes vital to basic development on the sex chromosomes. [3] [10]

Sex chromosome aneuploidies occur via a process known as non-disjunction, where chromosomes fail to divide properly during cell division and produce gametes, in this case sperm, with an abnormal number of chromosomes. [11] In the case of XYYY syndrome, the karyotype may be a result of non-disjunction with an XYY father, or of double non-disjunction resulting in a YYY sperm with a chromosomally normal father. [5] Non-disjunction can also arise during embryo development shortly after conception, which often gives rise to mosaicism. [1]

Diagnosis

Chromosome aneuploidies such as 48,XYYY are diagnosed via karyotype. [12] Rarely, XYYY syndrome has been detected prenatally via amniocentesis, though no prenatally diagnosed cases of XYYY syndrome have survived to birth. [13]

Epidemiology

XYYY syndrome is exceptionally rare. Only twelve cases have been reported in the medical literature, [8] in addition to four mosaic cases. [2] As the related XYY syndrome is much more common and has a mild to asymptomatic phenotype, it is speculated that there may be many undiagnosed cases of XYYY syndrome that are milder than those medically reported. [1]

History

XYYY syndrome was first recorded in 1965, when the 48,XYYY karyotype was found in a five-year-old boy evaluated for borderline intellectual disability. [14] Another case of non-mosaic 48,XYYY would not be reported until 1972, highlighting the rarity of the syndrome. [15] As karyotyping at the time was in its infancy, confirming many early cases was difficult; one early recorded case of a supposed 47,XYY/48,XYYY mosaic was found after further investigation to have an unrelated chromosomal rearrangement. [16] [17]

Early research into men with Y-chromosome polysomy was focused on the possibility for violent and criminal behaviour. Cases would be screened for in prisons and mental hospitals, creating a cycle of confirmation for the hypothesis that men with additional Y chromosomes were criminals by only searching for them in criminal populations. [16] [18] These assumptions would later be disproven by longitudinal studies of people diagnosed at birth with sex chromosome aneuploidies, which discovered that men with one additional Y chromosome had no particular criminal propensities and were barely distinguishable from the general population. However, as the only conditions to be found in such population surveys were Klinefelter's syndrome, trisomy X, and XYY syndrome, rarer conditions such as XYYY syndrome remain little-understood. [19]

Comparison with XYY syndrome

The much better-understood XYY syndrome occurs in approximately 1 in 1,000 males. [20] XYY syndrome is known to have a milder phenotype in cases found by chance, such as during prenatal screening, than in those karyotyped due to a medical or behavioural indication. [18] As all described cases of XYYY syndrome were ascertained due to a medical indication, it is unclear whether the relatively severe phenotype described in the medical literature is representative of all XYYY cases, or if there are milder cases that have not been brought to diagnostic attention. [1]

The two syndromes have a number of symptoms in common, such as tall stature (although the height increase in XYY appears greater than that in XYYY [1] [18] ) and behavioural issues. One significant observed distinction is that while males with 47,XYY karyotypes usually have normal fertility, 48,XYYY appears associated with infertility or sterility. The 47,XYY karyotype is associated with an increased expression of H-Y antigen, and the azoospermia observed in 48,XYYY subjects may in turn be associated with a higher expression of H-Y antigen than in 47,XYY. [5]

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">Trisomy</span> Abnormal presence of three copies of a particular chromosome

A trisomy is a type of polysomy in which there are three instances of a particular chromosome, instead of the normal two. A trisomy is a type of aneuploidy.

<span class="mw-page-title-main">Turner syndrome</span> Chromosomal disorder in which a female is partially or completely missing an X chromosome

Turner syndrome (TS), also known as 45,X, or 45,X0, is a genetic disorder in which a female has a single X chromosome, compared to the two sex chromosomes in most people. Signs and symptoms vary among those affected. Often, a short and webbed neck, low-set ears, low hairline at the back of the neck, short stature, and swollen hands and feet are seen at birth. Typically, those affected do not develop menstrual periods or breasts without hormone treatment and are unable to have children without reproductive technology. Heart defects, diabetes, and low thyroid hormone 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. Vision and hearing problems also occur more often than average.

<span class="mw-page-title-main">Aneuploidy</span> Presence of an abnormal number of chromosomes in a cell

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 any number of complete chromosome sets is called a euploid cell.

<span class="mw-page-title-main">Nondisjunction</span> Failure to separate properly during cell division

Nondisjunction is the failure of homologous chromosomes or sister chromatids to separate properly during cell division (mitosis/meiosis). There are three forms of nondisjunction: failure of a pair of homologous chromosomes to separate in meiosis I, failure of sister chromatids to separate during meiosis II, and failure of sister chromatids to separate during mitosis. Nondisjunction results in daughter cells with abnormal chromosome numbers (aneuploidy).

<span class="mw-page-title-main">Polysomy</span> Abnormal multiples of one or more chromosomes

Polysomy is a condition found in many species, including fungi, plants, insects, and mammals, in which an organism has at least one more chromosome than normal, i.e., there may be three or more copies of the chromosome rather than the expected two copies. Most eukaryotic species are diploid, meaning they have two sets of chromosomes, whereas prokaryotes are haploid, containing a single chromosome in each cell. Aneuploids possess chromosome numbers that are not exact multiples of the haploid number and polysomy is a type of aneuploidy. A karyotype is the set of chromosomes in an organism and the suffix -somy is used to name aneuploid karyotypes. This is not to be confused with the suffix -ploidy, referring to the number of complete sets of chromosomes.

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

XX male syndrome, also known as de la Chapelle syndrome, is a rare congenital intersex condition in which an individual with a 46, XX karyotype has phenotypically male characteristics that can vary among cases. Synonyms include 46,XX testicular difference of sex development, 46,XX sex reversal, nonsyndromic 46,XX testicular DSD, and XX sex reversal.

<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 2 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.

A chromosomal abnormality, chromosomal anomaly, chromosomal aberration, chromosomal mutation, or chromosomal disorder, is a missing, extra, or irregular portion of chromosomal DNA. These can occur in the form of numerical abnormalities, where there is an atypical number of chromosomes, or as structural abnormalities, where one or more individual chromosomes are altered. Chromosome mutation was formerly used in a strict sense to mean a change in a chromosomal segment, involving more than one gene. Chromosome anomalies usually occur when there is an error in cell division following meiosis or mitosis. Chromosome abnormalities may be detected or confirmed by comparing an individual's karyotype, or full set of chromosomes, to a typical karyotype for the species via genetic testing.

Patricia Ann Jacobs OBE FRSE FRS FMedSci FRCPath is a Scottish geneticist and is Honorary Professor of Human Genetics, Co-director of Research, Wessex Regional Genetics Laboratory, within the University of Southampton.

<span class="mw-page-title-main">Klinefelter syndrome</span> Human chromosomal condition

Klinefelter syndrome (KS), also known as 47,XXY, is an aneuploid genetic condition where a male has an additional copy of the X chromosome. The primary features are infertility and small, poorly functioning testicles. 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, less body hair, breast growth, and less interest in sex. Often, these symptoms are noticed only at puberty. Intelligence is usually average, but reading difficulties and problems with speech are more common.

The Focus Foundation, located in Davidsonville, Maryland, is a research foundation dedicated to identifying and assisting families and children who have X and Y Chromosomal Variations, dyslexia and/or developmental coordination disorder. These conditions can lead to language-based disabilities, motor planning deficits, reading dysfunction, and attention and behavioral disorders. The Focus Foundation believes that, through increased awareness, early identification, and specific and targeted treatment, children with these conditions can reach their full potential.

XXXY syndrome 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. This is called a mosaic karyotype because, like tiles in mosaic floors or walls, there is more than one type of cell. 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">17q12 microdeletion syndrome</span> Rare genetic anomaly in humans

17q12 microdeletion syndrome, also known as 17q12 deletion syndrome, is a rare chromosomal anomaly caused by the deletion of a small amount of material from a region in the long arm of chromosome 17. It is typified by deletion of the HNF1B gene, resulting in kidney abnormalities and renal cysts and diabetes syndrome. It also has neurocognitive effects, and has been implicated as a genetic factor for autism and schizophrenia.

<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.

<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">XYYYY syndrome</span> Rare chromosomal disorder

XYYYY syndrome, also known as 49,XYYYY, is an exceptionally rare chromosomal disorder in which a male human has three additional copies of the Y chromosome. Only seven non-mosaic cases of the disorder have ever been recorded in the medical literature, as well as five mosaic cases, of which two had more 48,XYYY than 49,XYYYY cells. Due to the extreme rarity of the disorder, little is understood about it, and the phenotype appears to be variable.

<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 it is rarely diagnosed; fewer than 10 per cent of those with the condition know they have it.

References

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  6. ↑ Ridler MAC, Lax R, Mitchell MJ, Shapiro A, Saldaña‐Garcia P (January 1973). "An adult male with XYYY sex chromosomes". Clinical Genetics. 4 (1): 69–77. doi:10.1111/j.1399-0004.1973.tb01125.x. PMID   4691557. S2CID   879069.
  7. ↑ Hori N, Kato T, Sugimura Y, Tajima K, Tochigi H, Kawamura J (1 May 1988). "A Male Subject with 3 Y Chromosomes (48,XYYY): A Case Report". Journal of Urology. 139 (5): 1059–1061. doi:10.1016/S0022-5347(17)42772-8. PMID   3361645.
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  10. ↑ Unique, Rooman R, Hultén M (2005). "Pentasomy X" (PDF). Unique. Retrieved 19 March 2021.
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  12. ↑ O'Connor C (2008). "Chromosomal Abnormalities: Aneuploidies". Nature Education. Retrieved 19 March 2021.
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  14. ↑ Townes PL, Ziegler NA, Lenhard L (15 May 1965). "A patient with 48 chromosomes (XYYY)". The Lancet. 285 (7394): 1041–1043. doi:10.1016/S0140-6736(65)91315-2. PMID   14283740.
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  17. ↑ Wiener S, Sutherland G, Bartholomew AA (1 March 1969). "A Murderer with 47,XYY and an Additional Autosomal Abnormality". Journal of Criminology. 2 (1): 20–28. doi:10.1177/000486586900200103. S2CID   57515740.
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  19. ↑ Robinson, Arthur; Lubs, Herbert A.; Bergsma, Daniel, eds. (1979). Sex chromosome aneuploidy: prospective studies on children. Birth defects original article series 15 (1). New York: Alan R. Liss. ISBN   978-0-8451-1024-9.
  20. ↑ "47,XYY syndrome". MedLine Plus. 8 September 2020. Retrieved 21 March 2021.
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