XYY syndrome

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XYY syndrome, also known as Jacobs syndrome and Superman syndrome, is an aneuploid genetic condition in which a male has an extra Y chromosome.<ref name=GHR2009/> There are usually few symptoms.<ref name=NORD2012>Template:Cite web</ref> These may include being taller than average and an increased risk of learning disabilities.<ref name=GHR2009/><ref name=NORD2012/> The person is generally otherwise normal, including typical rates of fertility.<ref name=GHR2009/>

The condition is generally not inherited but rather occurs as a result of a random event during sperm development.<ref name=GHR2009/> Diagnosis is by a chromosomal analysis, but most of those affected are not diagnosed within their lifetime.<ref name=NORD2012/> There are 47 chromosomes, instead of the usual 46, giving a 47,XYY karyotype.<ref name=GHR2009/>

Treatment may include speech therapy or extra help with schoolwork, and outcomes are generally positive.<ref name=NORD2012/> The condition occurs in about 1 in 1,000 male births.<ref name=GHR2009>Template:Cite web</ref> Many people with the condition are unaware that they have it.<ref name=GARD2017>Template:Cite web</ref> The condition was first described in 1961.<ref>Template:Cite book</ref>

Signs and symptoms

Physical traits

People with the 47,XYY karyotype have an increased growth rate from early childhood, with an average final height approximately Template:Convert above expected final height.<ref name="Nielsen 1998">Template:Cite web</ref> In Edinburgh, Scotland, eight 47,XYY boys born 1967–1972 and identified in a newborn screening programme had an average height of Template:Convert at age 18—their fathers' average height was Template:Convert, their mothers' average height was Template:Convert.<ref name="Gravholt 2013"/><ref name="Ratcliffe 1992">Template:Cite journal</ref> The increased gene dosage of three X/Y chromosome pseudoautosomal region (PAR1) SHOX genes has been postulated as a cause of the increased stature seen in all three sex chromosome trisomies: 47,XXX, 47,XXY, and 47,XYY.<ref name="SHOX">Template:Cite book p. 2304: Table 561-1. Differential diagnosis of tall stature and overgrowth syndromes. Postnatal overgrowth leading to childhood tall stature—includes: Klinefelter syndrome (XXY), SHOX excess syndromes, XYY.

Severe acne was noted in a very few early case reports, but dermatologists specializing in acne now doubt the existence of a relationship with 47,XYY.<ref name="Plewig 2000">Template:Cite book</ref>

Prenatal testosterone levels are normal in 47,XYY males.<ref>Template:Cite journal</ref> Most 47,XYY males have normal sexual development and have normal fertility.<ref name="Gravholt 2013"/><ref name="Milunsky 2010"/><ref name="Gardner 2004">Template:Cite book</ref><ref name="Gardner 2012">Template:Cite book</ref>

Cognitive and behavioral traits

In contrast to the other common sex chromosome aneuploidies—47,XXX and 47,XXY (Klinefelter syndrome)—the average of the IQ scores of 47,XYY boys identified by newborn screening programs was not reduced compared to the general population.<ref name="Bender 1986">Template:Cite book</ref><ref name="Leggett 2010">Template:Cite journal</ref> In a summary of six prospective studies of 47,XYY boys identified by newborn screening programmes, twenty-eight 47,XYY boys had an average 100.76 verbal IQ, 108.79 performance IQ, and 105.00 full-scale IQ.<ref name="Netley 1986">Template:Cite book</ref> In a systematic review including two prospective studies of 47,XYY boys identified by newborn screening programs and one retrospective study of 47,XYY men identified by screening men over Template:Convert in height, forty-two 47,XYY boys and men had an average 99.5 verbal IQ and 106.4 performance IQ.<ref name="Leggett 2010"/><ref name="Ratcliffe 1994">Template:Cite book</ref><ref name="Walzer 1991">Template:Cite book</ref><ref name="Theilgaard 1984">Template:Cite journal</ref>

In prospective studies of 47,XYY boys identified by newborn screening programs, the IQ scores of 47,XYY boys were usually slightly lower than those of their siblings.<ref name="Gravholt 2013"/><ref name="Robinson 1985">Template:Cite book</ref> In Edinburgh, fifteen 47,XYY boys with siblings identified in a newborn screening program had an average 104.0 verbal IQ and 106.7 performance IQ, while their siblings had an average 112.9 verbal IQ and 114.6 performance IQ.<ref name="Ratcliffe 1994"/>

Approximately half of 47,XYY boys identified by newborn screening programs had learning difficulties—a higher proportion than found among siblings and above-average-IQ control groups.<ref name="Gravholt 2013"/><ref name="Gardner 2012"/> In Edinburgh, 54% of 47,XYY boys (7 of 13) identified in a newborn screening program received remedial reading teaching compared to 18% (4 of 22) in an above-average-IQ control group of 46,XY boys matched by their father's social class.<ref name="Ratcliffe 1994"/> In Boston, USA 55% of 47,XYY boys (6 of 11) identified in a newborn screening program had learning difficulties and received part-time resource room help compared to 11% (1 of 9) in an above-average-IQ control group of 46,XY boys with familial balanced autosomal chromosome translocations.<ref name="Walzer 1991"/>

Developmental delays and behavioral problems are also found, but these characteristics vary widely among affected boys and men, are not unique to 47,XYY and are managed no differently from in 46,XY males.<ref name="Milunsky 2010"/> Aggression is not seen more frequently in 47,XYY males.<ref name="Gravholt 2013"/><ref name="Milunsky 2010"/>

Patients with XYY syndrome have been shown to have a higher risk of developing certain diseases such as asthma, seizure problems, and tremors. Some 47,XYY patients have been found to have genitourinary malformations. These include cryptorchidism, hypoplastic scrotum, microphallus, and hypospadias.<ref name="Bardsley 2013">Template:Cite journal</ref> These men could be diagnosedTemplate:What with infertility as a result of oligospermia or sperm chromosomal abnormalities.<ref name="Milunsky 2010"/> According to certain psychological studies, people with XYY syndrome may have problems with impulse control and emotional regulation.<ref name="Milunsky 2010"/> Increased testosterone levels were found to be correlated with an increased risk of aggressive behavior in incarcerated males with 47,XYY syndrome.<ref name="Bardsley 2013"/>

File:XYY syndrome.svg
Diagram showing XYY syndrome formation. MI and MII are the stages of meiosis, while the blue and pink circles are male (sperm) and female (ovum) cells, respectively, and the blue and pink bars are Y- and X-chromosomes, respectively. The purple cell has 2 Y-chromosomes and 1 X-chromosome caused by the ovum fusing with a sperm cell with two Y-chromosomes, which was due to division problems in MII of the male.

47,XYY is not inherited; it usually occurs as a random event during the formation of sperm cells. An incident in chromosome separation during anaphase II (of meiosis II) called nondisjunction can result in sperm cells with an extra copy of the Y-chromosome. If one of these atypical sperm cells contributes to the genetic makeup of a child, the child will have an extra Y-chromosome in each of the body's cells.<ref name="Robinson 1999">Template:Cite journal</ref>

In some cases, the extra Y-chromosome results from nondisjunction during mitosis in early embryonic development. This can produce 46,XY/47,XYY mosaics.<ref name="Robinson 1999"/>

Diagnosis

47,XYY syndrome is not usually diagnosed until learning issues are present. The syndrome is diagnosed in an increasing number of children prenatally by amniocentesis and chorionic villus sampling<ref>Template:Cite book</ref> in order to obtain a chromosome karyotype, where the abnormality can be observed.

It is estimated that only 15–20% of children with 47,XYY syndrome are ever diagnosed. Of these, approximately 30% are diagnosed prenatally. For the rest of those diagnosed after birth, around half are diagnosed during childhood or adolescence after developmental delays are observed. The rest are diagnosed after any of a variety of symptoms, including fertility problems (5%)<ref>Template:Cite book</ref> have been seen.

Epidemiology

Around 1 in 1,000 boys are born with a 47,XYY karyotype.<ref name="Gravholt 2013"/><ref name="Milunsky 2010"/> The incidence of 47,XYY is not known to be affected by the parents' ages.<ref name="Gravholt 2013"/><ref name="Milunsky 2010"/>

History

1960s

In April 1956, Hereditas published the discovery by cytogeneticists Joe Hin Tjio and Albert Levan at Lund University in Sweden that the normal number of chromosomes in diploid human cells was 46—not 48, as had been believed for the preceding thirty years.<ref>Template:Cite journal</ref> In the wake of the establishment of the normal number of human chromosomes, 47,XYY was the last of the common sex chromosome aneuploidies to be discovered, two years after the discoveries of 47,XXY,<ref>Template:Cite journal</ref> 45,X<ref>Template:Cite journal</ref> and 47,XXX<ref>Template:Cite journal</ref> in 1959. Even the much less common 48,XXYY<ref>Template:Cite journal</ref> had been discovered in 1960, a year before 47,XYY.

Screening for those X chromosome aneuploidies was possible before the advent of human chromosome analysis by noting the presence or absence of "female" sex chromatin bodies (Barr bodies) in the nuclei of interphase cells in buccal smears, a technique developed a decade before the first reported sex chromosome aneuploidy.<ref name="Barr 1949">Template:Cite journal</ref> An analogous technique to screen for Y-chromosome aneuploidies by noting supernumerary "male" sex chromatin bodies was not developed until 1970, a decade after the first reported male sex chromosome aneuploidy.<ref name="pursuit 1970">Template:Cite journal

The first published report of a man with a 47,XYY karyotype was by the American cytogeneticist Avery Sandberg and his colleagues at Roswell Park Comprehensive Cancer Center (then known as Roswell Park Memorial Institute) in Buffalo, New York in 1961. It was an incidental finding in a normal 44-year-old, 6 ft. [183 cm] tall man of average intelligence who was karyotyped because he had a daughter with Down syndrome.<ref name="Sandberg 1961">Template:Cite journal

  • Template:Cite journal</ref> Only a dozen isolated 47,XYY cases were reported in the medical literature in the four years following the first report by Sandberg.<ref name="Court Brown 1968">Template:Cite journal</ref>

The XYY syndrome, if named after the discoverer, should rightly be termed Sandberg syndrome and not Jacobs syndrome although the British cytogeneticist Patricia Jacobs did indeed contribute meaningfully to medical knowledge of XYY. In December 1965 and March 1966, Nature and The Lancet published the first preliminary reports by Jacobs and her colleagues at the MRC Human Genetics Unit at Western General Hospital in Edinburgh of a chromosome survey of 315 male patients at State Hospital in Carstairs, Lanarkshire—Scotland's only special security hospital for developmentally disabled people —that found nine patients, ages 17 to 36, averaging almost 6 ft. in height (avg. 5'11", range: 5'7" to 6'2"), had a 47,XYY karyotype, and mischaracterized them as aggressive and violent criminals.<ref name="Court Brown 1968"/><ref>Template:Cite journal

In January 1968 and March 1968, The Lancet and Science published the first U.S. reports of tall, institutionalized XYY males by Mary Telfer, a biochemist, and colleagues at the Elwyn Institute.<ref name="Telfer 1968a">Template:Cite journal

  • Template:Cite journal</ref> Telfer found five tall, developmentally disabled XYY boys and men in hospitals and penal institutions in Pennsylvania, and since four of the five had at least moderate facial acne, reached the erroneous conclusion that acne was a defining characteristic of XYY males.<ref name="Telfer 1968a"/> After learning that convicted mass murderer Richard Speck had been karyotyped, Telfer not only incorrectly assumed the acne-scarred Speck was XYY, but reached the false conclusion that Speck was the archetypical XYY male—or "supermale" as Telfer referred to XYY males outside of peer-reviewed scientific journals.<ref>Template:Cite journalTemplate:Blockquote</ref>

In April 1968, The New York Times—using Telfer as a main source—introduced the XYY genetic condition to the general public in a three-part series on consecutive days that began with a Sunday front-page story about the planned use of the condition as a mitigating factor in two murder trials in Paris<ref name="Daniel Hugon">Daniel Hugon, Paris, France

In December 1968, the Journal of Medical Genetics published the first XYY review article—by Willam Michael Court Brown (1918–1969),<ref>The first XYY review article, by W. Michael Court Brown, a physician and world authority on radiation biology and cytogenetics, was published in December 1968. Court Brown had established the MRC Clinical Effects of Radiation Unit at Western General Hospital in Edinburgh in 1956, which was renamed the MRC Clinical and Population Cytogenetics Unit in 1967 (and subsequently renamed the MRC Human Genetics Unit in 1988). In 1962, Court Brown had been the first to suggest—based on findings of antisocial behavior in some institutionalized Klinefelter syndrome (47,XXY) patients and psychosis in some institutionalized Triple X syndrome (47,XXX) patients—that individuals with sex chromosome abnormalities could be held in law to suffer from diminished responsibility.

In May 1969, at the annual meeting of the American Psychiatric Association, Telfer and her Elwyn Institute colleagues reported that case studies of the institutionalized XYY and XXY males they had found convinced them that XYY males had been falsely stigmatized and that their behavior may not be significantly different from chromosomally normal 46,XY males.<ref>Template:Cite news

In June 1969, the National Institute of Mental Health (NIMH) Center for Studies of Crime and Delinquency held a two-day XYY conference in Chevy Chase, Maryland.<ref>Template:Cite book June 19–20, 1969 XYY conference.</ref> In December 1969, with a grant from the NIMH Center for Studies of Crime and Delinquency, cytogeneticist Digamber Borgaonkar at Johns Hopkins Hospital began a chromosome survey of (predominantly African-American) boys ages 8 to 18 in all Maryland institutions for delinquent, neglected, or mentally ill juveniles, which was suspended from February–May 1970 due to an American Civil Liberties Union (ACLU) lawsuit regarding the study's lack of informed consent.<ref name="Pyeritz 1977">Template:Cite book</ref><ref>Template:Cite news

In the late 1960s and early 1970s, screening of consecutive newborns for sex chromosome abnormalities was undertaken at seven centers worldwide: in Denver (Jan 1964–1974), Edinburgh (Apr 1967–Jun 1979), New Haven (Oct 1967–Sep 1968), Toronto (Oct 1967–Sep 1971), Aarhus (Oct 1969–Jan 1974, Oct 1980–Jan 1989), Winnipeg (Feb 1970–Sep 1973), and Boston (Apr 1970–Nov 1974).<ref name="March of Dimes">Template:Cite book

1970s

In December 1969, Lore Zech at the Karolinska Institute in Stockholm first reported intense fluorescence of the A T-rich distal half of the long arm of the Y chromosome in the nuclei of metaphase cells treated with quinacrine mustard.<ref name="Zech 1969">Template:Cite journal</ref> In April 1970, Peter Pearson and Martin Bobrow at the MRC Population Genetics Unit in Oxford and Canino Vosa at the University of Oxford reported fluorescent "male" sex chromatin bodies in the nuclei of interphase cells in buccal smears treated with quinacrine dihydrochloride, which could be used to screen for Y chromosome aneuploidies like 47,XYY.<ref name="Pearson 1970">Template:Cite journal

In December 1970, at the annual meeting of the American Association for the Advancement of Science (AAAS), its retiring president, geneticist H. Bentley Glass, cheered by the legalization of abortion in New York,<ref> Template:Cite news

  • Template:Cite news</ref> envisioned a future where pregnant women would be required by the government to abort XYY "sex deviants".<ref name="Pyeritz 1977"/><ref>

Template:Cite news

In 1973, child psychiatrist Herbert Schreier at Children's Hospital told Harvard Medical School microbiologist Jon Beckwith of Science for the People that he thought Walzer's Boston XYY study was unethical; Science for the People investigated the study and, regarding the study, filed an ethics complaint with Harvard Medical School in March 1974.<ref name="Beckwith 2002"/> In November 1974, Science for the People went public with their objections to the Boston XYY study in a press conference and a New Scientist article alleging inadequate informed consent, a lack of benefit (since no specific treatment was available) but substantial risk (by stigmatization with a false stereotype) to the subjects, and that the unblinded experimental design could not produce meaningful results regarding the subjects' behavior.<ref name="Boston"/> In December 1974, the Harvard Standing Committee on Medical Research issued a report supporting the Boston XYY study, and in March 1975, the faculty voted 199–35 to allow continuation of the study.<ref name="Boston"/> After April 1975, screening of newborns was discontinued—changes to informed consent procedures and pressure from additional advocacy groups, including the Children's Defense Fund, having led to the discontinuation of the last active U.S. newborn screening programs for sex chromosome abnormalities in Boston and Denver.<ref name="Boston"/>

In a paper published in New Scientist on November 14, 1974 entitled "XYY syndrome: a dangerous myth" found no link was found between having an extra Y chromosome and violent behavior. According to the paper, adolescents found to have an extra Y chromosome in a Maryland institution were chemically sterilized to attempt to maintain "normal behavior," despite this the paper found no major behavioral differences between XY and XYY individuals.<ref>Template:Cite web</ref>

In August 1976, Science published a retrospective cohort study by Educational Testing Service psychologist Herman Witkin and colleagues that screened the tallest 16% of men (over 184 cm (6'0") in height) born in Copenhagen from 1944 to 1947 for XXY and XYY karyotypes, and found an increased rate of minor criminal convictions for property crimes among sixteen XXY and twelve XYY men may be related to the lower intelligence of those with criminal convictions, but found no evidence that XXY or XYY men were inclined to be aggressive or violent.<ref name="Witkin 1976">Template:Cite journal

1980s and later

The March of Dimes sponsored five international conferences in June 1974, November 1977, May 1981, June 1984, and June 1989 and published articles from the conferences in book form in 1979, 1982, 1986, and 1991 from seven longitudinal prospective cohort studies on the development of over 300 children and young adults with sex chromosome abnormalities identified in the screening of almost 200,000 consecutive births in hospitals in Denver, Edinburgh, New Haven, Toronto, Aarhus, Winnipeg, and Boston from 1964 to 1975.<ref name="March of Dimes"/><ref>The five March of Dimes international conferences and four books also included reports on the findings of longitudinal prospective studies in London, Ontario and Tokyo on the development of children and with sex chromosome abnormalities identified in part by newborn screening programs.</ref> These seven studies—the only unbiased studies of unselected individuals with sex chromosome abnormalities—have replaced the older, biased studies of institutionalized individuals in understanding the development of individuals with sex chromosome abnormalities.<ref name="Milunsky 2010"/><ref>The last active longitudinal prospective study ended in 2000 with the end of the 36-year Denver study following the death of pediatrician and geneticist Arthur Robinson.

In May 1997, Nature Genetics published the discovery by Ercole Rao and colleagues of the X/Y chromosome pseudoautosomal region (PAR1) SHOX gene, haploinsufficiency of which leads to short stature in Turner syndrome (45,X).<ref name="Rao 1997">Template:Cite journal</ref> It was subsequently postulated that the increased gene dosage of three SHOX genes leads to tall stature in the sex chromosome trisomies 47,XXX, 47,XXY, and 47,XYY.<ref name="SHOX"/>

In July 1999, Psychological Medicine published a case-control study by Royal Edinburgh Hospital psychiatrist Michael Götz and colleagues that found an increased rate of criminal convictions among seventeen XYY men identified in the Edinburgh newborn screening study compared to an above-average-IQ control group of sixty XY men, which multiple logistic regression analysis indicated was mediated mainly through lowered intelligence.<ref name="Götz 1999"> Template:Cite journal</ref>

In June 2002, the American Journal of Medical Genetics published results from a longitudinal prospective cohort Denver Family Development Study led by pediatrician and geneticist Arthur Robinson,<ref name="Robinson 1990">Template:Cite journal</ref> which found that in fourteen prenatally diagnosed 47,XYY boys (from high socioeconomic status families), IQ scores available for six boys ranged from 100 to 147 with a mean of 120.<ref name="Linden 2002">Template:Cite journal</ref> For the eleven of fourteen boys with siblings, in nine instances their siblings were stronger academically, but in one case the subject was performing equal to, and in another case superior to, his siblings.<ref name="Linden 2002"/>

Society and culture

Some medical geneticists question whether the term "syndrome" is appropriate for this condition<ref name="Gravholt 2013">Template:Cite book</ref> because many people with this karyotype appear normal.<ref name="Gravholt 2013"/><ref name="Milunsky 2010">Template:Cite book</ref>

In June 1970, The XYY Man was published—the first of seven Kenneth Royce spy novels whose fictional tall, intelligent, nonviolent XYY hero was a reformed expert cat burglar recruited by British intelligence for dangerous assignments—and later adapted into a thirteen-episode British summer television series broadcast in 1976 and 1977.<ref>Template:Cite book

In other fictional television works, a January 1971 episode "By the Pricking of My Thumbs ..." of the British science fiction TV series Doomwatch featured an XYY boy expelled from school because his genetic condition led him to be falsely accused of nearly blinding another boy.<ref name="By the Pricking of My Thumbs ...">Template:Cite book By the Pricking of My Thumbs ... written by Robin Chapman. Sixteen-year-old Stephen Franklin is expelled from school because, his father says, he has an obscure genetic defect—an extra "Y" chromosome.</ref> A November 1993 episode of the American police procedural TV series Law & Order, "Born Bad", portrays a 14-year-old XYY sociopathic murderer.<ref name="Born Bad">Template:Cite news One of TV's most consistently rewarding series takes a grim and unforgettable detour into the bleak mindset of a teen-age sociopathic murderer. Is society to blame, or as his lawyer argues, is he genetically predisposed to violence, with an extra "Y" chromosome? … the boy's hopeless future seems all too evident.</ref> The May 2007 season finale episode, "Born To Kill", of the American police procedural TV series CSI: Miami depicts a 34-year-old XYY serial killer.<ref name="Born To Kill">Template:Cite journal There's nothing funny about the season finale. That episode is about a serial killer with "criminal" genes. "It's a real-life natural-born killer situation", executive producer Ann Donahue says. "Usually girls have XX chromosomes and boys have XY, but this killer is XYY, which means too much testosterone." Among other niceties, the killer who has ties to Boston… brands his female victims with the letter Y.</ref>

The false stereotype of XYY boys and men as violent criminals has also been used as a plot device in the horror films Il gatto a nove code in February 1971 (dubbed into English as The Cat o' Nine Tails in May 1971) and Alien 3 in May 1992.<ref name="Green 1985"/><ref name="Beckwith 2002"/> The main character of the 2005 film Neo Ned is a neo-nazi who has an extra Y chromosome.<ref>Template:Cite AV media

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See also

References

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