XXXYY syndrome

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XXXYY syndrome
Other names49,XXXYY
XXXYY syndrome karyotype.jpg
Karyotype of XXXYY syndrome
Specialty Medical genetics   OOjs UI icon edit-ltr-progressive.svg
Symptoms Intellectual disability, facial dysmorphisms, genital anomalies
Usual onsetConception
DurationLifelong
Causes Nondisjunction
Diagnostic method Karyotype

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.

Contents

XXXYY syndrome was first recorded in 1963. Its long-term prognosis is poorly understood; while the condition as reported in the medical literature is relatively severe, it is unknown if there are milder cases that have not come to diagnostic attention.

Presentation

Due to its exceptional rarity, little is known about XXXYY syndrome. There are no unbiased descriptions of the disorder; all living XXXYY males reported in the medical literature were diagnosed after birth due to symptoms, and it is unknown if there are milder cases that have not come to diagnostic attention. [1] [2] [3] All known cases of the syndrome have been associated with developmental delay or intellectual disability. [1] [2] Adult XXXYY men have generally been reported as having moderate to severe intellectual disability; [1] moderate intellectual disability is defined by an adult cognitive capacity similar to that of a six- to eight-year-old and the ability to acquire basic living and employment skills with support, while the severe form is associated with an adult capability similar to that of a three- to five-year-old, with long-term dependence on caregivers. [4]

Sex chromosome aneuploidies [note 1] are generally associated with tall stature, particularly polysomies of the Y chromosome, but data on tetrasomy and pentasomy disorders [note 2] is less clear and some seem associated with short stature; [6] [7] adult XXXYY men in the medical literature have ranged in height from 170 centimetres (5 ft 7 in) to 192 centimetres (6 ft 4 in). [1] The disorder seems associated with dysmorphic features (unusual facial features), with reported examples including hypertelorism (wide-spaced eyes), a prominent forehead and wide nasal bridge, epicanthic folds, and micrognathia (small chin). [1] [2] [3] Other unusual features reported include clinodactyly (incurved pinky fingers) and radioulnar synostosis (fusion of the long bones in the forearm). These findings are common to sex chromosome aneuploidies. [2] [8] XXXYY syndrome is thought to be associated with similar congenital issues to other sex chromosome tetrasomy and pentasomy disorders, such as heart and kidney malformations, dental issues, and minor facial dysmorphology. [1]

As very few cases of XXXYY syndrome in adult men have been reported, drawing conclusions about physical development and hormonal functioning is difficult. Only one XXXYY man recorded in the medical literature has undergone hormone testing. He was found to have low testosterone, alongside elevated lutenizing hormone and follicle stimulating hormone. [1] According to literature reviews, genital abnormalities are a hallmark of the syndrome. Reported findings include micropenis and cryptorchidism (undescended testes). [1] [2] [3] Adults generally have sparse or absent facial hair. Some men have been described as having high-pitched voices. [2]

Little is understood about the psychological and behavioural phenotype of XXXYY syndrome. One review described behaviour as "generally passive", a common description of people with X-chromosome polysomy. [3] The literature is divided on whether autism or autistic features are common, though they have been reported in other X- and Y-chromosome disorders. Behavioural "outbursts" are mentioned by two reviews. [1] [2] [3] X- and Y-chromosome polysomies are both associated with behavioural and psychological sequelae. Because XXXYY syndrome involves both X and Y polysomy, it is unclear what effects are caused by each. [3]

Causes

XXXYY syndrome is caused by two extra copies of the X chromosome alongside one extra copy of the Y chromosome, producing a total complement of 49 chromosomes rather than the usual 46. [1] Sex chromosome aneuploidies are the most frequent form of aneuploidy in humans. [9] Though a 48-chromosome complement involving the autosomes would be unsurvivable, 49,XXXYY and other high-level sex chromosome aneuploidies, such as tetrasomy X, pentasomy X, XYYY syndrome, XYYYY syndrome, and XXXXY syndrome, are survivable with relatively mild phenotypes due to the paucity of genes vital to basic development on the sex chromosomes. [3]

Sex chromosome aneuploidies are caused by nondisjunction, a process through which gametes (eggs or sperm) with too many or too few chromosomes are produced. In nondisjunction, homologous chromosomes or sister chromatids fail to separate properly when producing gametes. [10] XXXYY syndrome, by its nature, requires multiple steps of nondisjunction. Possible causes include fertilization of a normal egg by an XXYY sperm, fertilization of an XX egg by an XYY sperm, or fertilization of an XXX egg by a YY sperm. [2] Nondisjunction is generally a random event not related to any characteristic of the parents, and almost never recurs in their future children. [11]

Diagnosis

Chromosome aneuploidies such as XXXYY syndrome are diagnosed through the process of karyotyping, or chromosome testing. [12] One recorded case of the disorder was diagnosed prenatally via amniocentesis, but did not survive to birth; all other reported cases of XXXYY syndrome were diagnosed postnatally. [2] [13] Sex chromosome aneuploidies can only be diagnosed via conclusive genetic testing, not on the basis of clinical examination, due to their nonspecific phenotypes. Such disorders are underdiagnosed, and when diagnosis does occur, it is often late. [1] [3]

Prognosis

The long-term prognosis of XXXYY syndrome is little-understood. Few adults with the disorder have been reported, and there are no reports of people diagnosed prenatally who survived to birth. This lack of prognosis information is common in sex chromosome tetrasomy and pentasomy; though longitudinal studies exist for the sex chromosome trisomies, higher-level aneuploidies are far rarer and information more sparse. Good prognosis appears linked to strong parental and personal support; people with such disorders whose caregivers have acted as advocates for their success have been reported as achieving at higher personal and social levels than the general portrait in the medical literature. [1] [2] [3]

Epidemiology

XXXYY syndrome is exceptionally rare. Only eight cases of the condition have been reported in the medical literature, and the prevalence is estimated to be below 1 in 1000000 [1] [2] Sex chromosome tetrasomy and pentasomy disorders are thought to be underdiagnosed, and people may exist who have milder versions of such conditions than are generally reported. [3] XXXYY syndrome only occurs in males, as the Y chromosome is in most cases necessary for male sexual development; this is not changed by the presence of multiple X chromosomes. [14] [15]

History

XXXYY syndrome was first recorded in 1963, in a 26-year-old man with a moderate intellectual disability living at the Utah State Training School who was ascertained due to having physical traits of Klinefelter syndrome. By that time, three men with XXYY syndrome had been reported. [16] 49,XXXYY was one of the later sex chromosome aneuploidies to be discovered, being preceded by Turner, [17] Klinefelter, [18] and trisomy X [19] in 1959, XXYY syndrome in 1960, [20] and XYY [21] and tetrasomy X [22] in 1961. The 49,XXXYY karyotype was not reported again until 1974, highlighting the rarity of the syndrome. [23] By the time of Linden, Bender, and Robinson's seminal review of sex chromosome tetrasomy and pentasomy in 1995, five cases of XXXYY syndrome had been reported. [3] As of 2023, three cases of XXXYY syndrome have been diagnosed in the 21st century. [2]

Early research on sex chromosome aneuploidies suffered from ascertainment bias. Patients were screened in prisons and institutions, forming an image of such conditions as severely disabling. This was particularly marked for Y-chromosome polysomy; early research into men with extra Y chromosomes focused on criminality, depicting such men as inclined to violent and unlawful behaviour. These assumptions were later disproven by longitudinal studies of people diagnosed at birth with sex chromosome trisomies, which found people with 47,XXY, 47,XXX, and 47,XYY karyotypes blended into the general population and had little unusual propensity for criminality. Despite these advances regarding sex chromosome trisomies, the tetrasomy and pentasomy variants remain understudied. Due to their extreme rarity, none were detected in these cohort studies, and no unbiased information exists on their long-term prognosis. [3] [24]

Notes

  1. ↑ Aneuploidy is the presence of too many or too few chromosomes in a cell. [5]
  2. ↑ In the context of sex chromosome disorders specifically, tetrasomy refers to karyotypes with four sex chromosomes, and pentasomy to ones with five. [3]

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">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">Trisomy 18</span> Chromosomal disorder in which there are three copies of chromosome 18

Trisomy 18, also known as Edwards syndrome, is a genetic disorder caused by the presence of a third copy of all or part of chromosome 18. Many parts of the body are affected. Babies are often born small and have heart defects. Other features include a small head, small jaw, clenched fists with overlapping fingers, and severe intellectual disability.

<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">Small supernumerary marker chromosome</span> Abnormal partial or mixed chromosome

A small supernumerary marker chromosome (sSMC) is an abnormal extra chromosome. It contains copies of parts of one or more normal chromosomes and like normal chromosomes is located in the cell's nucleus, is replicated and distributed into each daughter cell during cell division, and typically has genes which may be expressed. However, it may also be active in causing birth defects and neoplasms. The sSMC's small size makes it virtually undetectable using classical cytogenetic methods: the far larger DNA and gene content of the cell's normal chromosomes obscures those of the sSMC. Newer molecular techniques such as fluorescence in situ hybridization, next generation sequencing, comparative genomic hybridization, and highly specialized cytogenetic G banding analyses are required to study it. Using these methods, the DNA sequences and genes in sSMCs are identified and help define as well as explain any effect(s) it may have on individuals.

<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">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.

The Pallister–Killian syndrome (PKS), also termed tetrasomy 12p mosaicism or the Pallister mosaic aneuploidy syndrome, is an extremely rare and severe genetic disorder. PKS is due to the presence of an extra and abnormal chromosome termed a small supernumerary marker chromosome (sSMC). sSMCs contain copies of genetic material from parts of virtually any other chromosome and, depending on the genetic material they carry, can cause various genetic disorders and neoplasms. The sSMC in PKS consists of multiple copies of the short arm of chromosome 12. Consequently, the multiple copies of the genetic material in the sSMC plus the two copies of this genetic material in the two normal chromosome 12's are overexpressed and thereby cause the syndrome. Due to a form of genetic mosaicism, however, individuals with PKS differ in the tissue distributions of their sSMC and therefore show different syndrome-related birth defects and disease severities. For example, individuals with the sSMC in their heart tissue are likely to have cardiac structural abnormalities while those without this sSMC localization have a structurally normal heart.

<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.

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

Klinefelter syndrome (KS), also known as 47,XXY, is a chromosome anomaly where a male has an extra X chromosome. These complications commonly include infertility and small, poorly functioning testicles. 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.

<span class="mw-page-title-main">Tetrasomy 9p</span> Presence of four copies of the short arm of chromosome 9

Tetrasomy 9p is a rare chromosomal disorder characterized by the presence of two extra copies of the short arm of chromosome 9, in addition to the usual two. Symptoms of tetrasomy 9p vary widely among affected individuals but typically include varying degrees of delayed growth, abnormal facial features and intellectual disability. Symptoms of the disorder are comparable to those of trisomy 9p.

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.

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.

<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.

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

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