XXYY syndrome

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XXYY syndrome
Other names48,XXY Y Klinefelter syndrome (archaic); 48,XXYY variant of Klinefelter's syndrome (archaic) [1]
XXYY syndrome.svg
XXYY syndrome

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. [2]

Contents

Presentation

Very frequent signs and symptoms of this condition include the following: [3]

Other frequent signs of this condition include the following: [3]

Other symptoms may include the following:

Cause

48,XXYY syndrome is a condition related to the X and Y chromosomes (the sex chromosomes). People normally have 46 chromosomes in each cell. Two of the 46 chromosomes, known as X and Y, are called sex chromosomes because they help determine whether a person will develop male or female sex characteristics. Females typically have two X chromosomes (46,XX), and males have one X chromosome and one Y chromosome (46,XY). 48,XXYY syndrome results from the presence of an extra copy of both sex chromosomes in each of a male's cells (48,XXYY). Extra copies of genes on the X chromosome interfere with male sexual development, preventing the testes from functioning normally and reducing the levels of testosterone. Many genes are found only on the X or Y chromosome, but genes in areas known as the pseudoautosomal regions are present on both sex chromosomes. Extra copies of genes from the pseudoautosomal regions of the extra X and Y chromosome contribute to the signs and symptoms of 48,XXYY syndrome; however, the specific genes have not yet been identified. [4] [5]

Genetics

The condition 48,XXYY is not inherited; it usually occurs as a random event during the formation of reproductive cells (eggs and sperm). An error in cell division called nondisjunction results in a reproductive cell with an abnormal number of chromosomes. In 48,XXYY syndrome, the extra sex chromosomes almost always comes from a sperm cell. Nondisjunction may cause a sperm cell to gain two extra sex chromosomes, resulting in a sperm cell with three sex chromosomes (one X and two Y chromosomes). If that sperm cell fertilizes a normal egg cell with one X chromosome, the resulting child will have two X chromosomes and two Y chromosomes in each of his body's cells.[ citation needed ]

In a small percentage of cases, 48,XXYY syndrome results from nondisjunction of the sex chromosomes in a 46,XY embryo very soon after fertilization has occurred. This means that a normal sperm cell with one Y chromosome fertilized a normal egg cell with one X chromosome, but right after fertilization, nondisjunction of the sex chromosomes caused the embryo to gain two extra sex chromosomes, resulting in a 48,XXYY embryo. [4]

Diagnosis

A karyotype is done to diagnose XXYY syndrome. Treatment consists of medications, behavioral therapies, and intensive community support. [6]

Management

Patients generally need to be followed by an endocrinologist. If hypogonadism is present, testosterone treatment should be considered in all individuals regardless of cognitive abilities due to positive effects on bone health, muscle strength, fatigue, and endurance, with possible mental health/behavioral benefits, as well. [2]

Most children with XXYY have some developmental delays and learning disabilities. Therefore, these aspects should be checked and monitored: psychology (cognitive and social–emotional development), speech/language therapy, occupational therapy, and physical therapy. Consultation with a developmental pediatrician, psychiatrist, or neurologist to develop a treatment plan including therapies, behavioral interventions, educational supports, and psychotropic medications for behavioral and psychiatric symptoms should be arranged.[ citation needed ]

Common diagnoses such as learning disability/ID, ADHD, autism spectrum disorders, mood disorders, tic disorders, and other mental health problems should be considered, screened for, and treated. Good responses to standard medication treatments for inattention, impulsivity, anxiety, and mood instability are seen in this group, and such treatment can positively impact academic progress, emotional wellbeing, and long-term outcome. Poor fine-motor coordination and the development of intention tremor can make handwriting slow and laborious, and occupational therapy and keyboarding should be introduced at an early age to facilitate schoolwork and self-help skills. Educational difficulties should be evaluated with a full psychological evaluation to identify discrepancies between verbal and performance skills and to identify individual academic needs.[ citation needed ]

Expressive language skills are often affected throughout life, and speech therapy interventions targeting expressive language skills, dyspraxia, and language pragmatics may be needed into adulthood. Adaptive skills (life skills) are a significant area of weakness, necessitating community-based supports for almost all individuals in adulthood. [2] Additional treatment recommendations based on the individual strengths and weaknesses in XXYY syndrome may be required. [7]

Prognosis

Patients have an essentially normal life expectancy, but require regular medical follow-ups. [8] [4]

History

The first published report of a boy with a 48,XXYY karyotype was by Sylfest Muldal and Charles H. Ockey in Manchester, England in 1960. [9] It was described in a 15-year-old mentally disabled boy who showed signs of Klinefelter syndrome; however, chromosome testing revealed 48,XXYY instead of the 47, XXY arrangement known to cause Klinefelter syndrome. Because of this, 48,XXYY syndrome was originally considered a variation of Klinefelter syndrome. Shared physical and medical features resulting from the presence of an extra X chromosome include tall stature, the development of testosterone deficiency in adolescence and/or adulthood (hypergonadotropic hypogonadism), and infertility. However, recent research shows some important differences in males with 48,XXYY compared to 47, XXY. [6] The most important differences result from the effects of the extra X and Y chromosome on neurodevelopment, leading to higher rates of developmental delays in early childhood, learning disability or intellectual disability, adaptive functioning (life skills) difficulties, neurodevelopmental disorders such as ADHD or autism spectrum disorders, and psychological/behavioral problems including anxiety, depression, and mood dysregulation. Also, a larger percentage of males with XXYY have additional medical problems such as seizures, congenital elbow malformations (radioulnar synostosis), and tremor compared to males with XXY. XXYY is still considered a variation of Klinefelter syndrome by some definitions, mainly because the pathophysiology of the testicular dysfunction has not been shown to differ from 47, XXY, and the most current research does not suggest that there should be any differences in the evaluation and treatment of testosterone deficiency in 48,XXYY compared to 47, XXY. [10] However, for the psychological and behavioral symptoms of XXYY syndrome, more extensive evaluations, interventions, and supports are usually needed compared to 47, XXY due to more complex neurodevelopmental involvement. Significant variability is seen between individuals in the number and severity of the medical and neurodevelopmental problems associated with XXYY, and some individuals have mild symptoms, while others are more significantly affected. [2]

See also

Related Research Articles

<span class="mw-page-title-main">Genetic disorder</span> Health problem caused by one or more abnormalities in the genome

A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosomal abnormality. Although polygenic disorders are the most common, the term is mostly used when discussing disorders with a single genetic cause, either in a gene or chromosome. The mutation responsible can occur spontaneously before embryonic development, or it can be inherited from two parents who are carriers of a faulty gene or from a parent with the disorder. When the genetic disorder is inherited from one or both parents, it is also classified as a hereditary disease. Some disorders are caused by a mutation on the X chromosome and have X-linked inheritance. Very few disorders are inherited on the Y chromosome or mitochondrial DNA.

<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">XY sex-determination system</span> Method of determining sex

The XY sex-determination system is a sex-determination system used to classify many mammals, including humans, some insects (Drosophila), some snakes, some fish (guppies), and some plants. In this system, the sex of an individual is determined by a pair of sex chromosomes. In most cases, females have two of the same kind of sex chromosome (XX), and are called the homogametic sex. Males have two different kinds of sex chromosomes (XY), and are called the heterogametic sex.

<span class="mw-page-title-main">X chromosome</span> Sex chromosome present in both sexes in the XY and X0 sex-determination systems

The X chromosome is one of the two sex chromosomes in many organisms, including mammals, and is found in both males and females. It is a part of the XY sex-determination system and XO sex-determination system. The X chromosome was named for its unique properties by early researchers, which resulted in the naming of its counterpart Y chromosome, for the next letter in the alphabet, following its subsequent discovery.

<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).

Hypogonadism means diminished functional activity of the gonads—the testes 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 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">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">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.

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.

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.

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.

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.

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

References

  1. ↑ "48,XXYY syndrome | Genetic and Rare Diseases Information Center (GARD) – an NCATS Program". rarediseases.info.nih.gov. Archived from the original on 13 January 2020. Retrieved 19 May 2019.
  2. 1 2 3 4 Tartaglia N, Davis S, Hench A, et al. (June 2008). "A New Look at XXYY Syndrome: Medical and Psychological Features". American Journal of Medical Genetics Part A. 146A (12): 1509–22. doi:10.1002/ajmg.a.32366. PMC   3056496 . PMID   18481271.
  3. 1 2 "48,XXYY syndrome". Genetics and Rare Diseases Information Center. Retrieved 20 February 2023.
  4. 1 2 3 "48,XXYY syndrome". Genetics and Rare Diseases Information Center. NIH.
  5. ↑ "48,XXYY syndrome". Genetics Home Reference. NIH.
  6. 1 2 Brown, Phyllis (2007). "Researchers define characteristics, treatment options for XXYY Syndrome". University of California. Archived from the original on April 1, 2010. Retrieved November 6, 2009.
  7. ↑ Visootsak J, Rosner B, Dykens E, Tartaglia N, Graham JM, Jr (2007). "Behavioral phenotype of sex chromosome aneuploidies: 48, XXYY, 48, XXXY, and 49,XXXXY". American Journal of Medical Genetics Part A. 143A (11): 1198–1203. doi:10.1002/ajmg.a.31746. PMID   17497714. S2CID   25732790.
  8. ↑ Corsini, Carole; Sarda, Pierre. "48,XXYY syndrome". Orphanet .
  9. ↑ Muldal S, Ockey CH (August 27, 1960). "The "double male": a new chromosome constitution in Klinefelter's syndrome". Lancet . 276 (7147): 492–3. doi:10.1016/S0140-6736(60)91624-X.
  10. ↑ Cotran, Ramzi S.; Kumar, Vinay; Fausto, Nelson; Nelso Fausto; Robbins, Stanley L.; Abbas, Abul K. (2005). Robbins and Cotran pathologic basis of disease. St. Louis, Mo: Elsevier Saunders. p. 179. ISBN   978-0-7216-0187-8.
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