XXXY syndrome

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XXXY syndrome
Other names48,XXXY syndrome [1]

XXXYsyndrome is a genetic condition characterized by a sex chromosome aneuploidy, where individuals have two extra X chromosomes. [2] 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. [2] [3] 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. [3]

Contents

Signs and symptoms

The symptoms of 48,XXXY syndrome are similar to those of Klinefelter syndrome, though the symptoms are usually more severe in 48,XXXY syndrome. Like Klinefelter syndrome, the presence of additional X chromosomes affects the male reproductive system, can cause physical abnormalities, and can affect cognitive development. When comparing 47,XXY and 48,XXXY, there is a greater risk for congenital malformations and more medical problems in those with 48,XXXY. [3]

Reproductive

Those with XXXY syndrome can have testicular dysgenesis and hypergonadotrophic hypogonadism. [3] Testicular dysgenesis is a condition in which a male has incomplete or complete loss of spermatogenesis, so that the individual produces very low levels, or no sperm. [4] This results in infertility of that individual. [4] Hypergonadotrophic hypogonadism is a condition in which the function of the testes in males is reduced and can result in low levels of sex steroids produced like testosterone.[ citation needed ]

Physical

Males with 48,XXXY can have average or tall stature, which becomes more prominent in adulthood. Facial dysmorphism is common in males with 48,XXXY and can include increased distance between the eyes (hypertelorism), skin folds of the upper eyelid (epicanthal folds), up-slanting opening between the eyelids (palpebral fissures) and hooded eyelids. Other physical features include the fifth finger or "pinkie" to be bent inwards towards the fourth finger (clinodactyly), short nail beds, flat feet, double jointedness (hyperextensibility) and prominent elbows with cubitus varus where the arm rests closer to the body. Musculoskeletal features may include congenital elbow dislocation and the limited ability of the feet to roll inwards while walking and upon landing. [3] Micropenis is another common symptom of this syndrome. [5]

Individuals affected with XXXY are also prone to developing taurodontism, which often presents early in life, and can be an early indicator of XXY syndrome. [2] Those with this syndrome are also prone to hip dysplasia, and other joint abnormalities. [6] An individual’s symptoms vary due to differing androgen deficiencies, and also with alter with age. Prepubescent boys with XXXY syndrome may not differ in physical appearance from a child without the syndrome. This is likely because androgen levels do not differ among pre-pubescent boys, but a difference does arise as puberty progresses. [2] Those with XXXY syndrome may also experience feminine distribution of adipose tissue, and gynecomastia may also be present. [2] Tall stature is more likely to appear in adolescence, when androgen levels begin to differ between those with XXXY syndrome and those that do not have it.

Cognitive and developmental

Neurological effects are believed to be more severe as the number of extra X chromosomes increases; a male with 48,XXXY is likely to have more severe symptoms than a male with Klinefelter syndrome. [5] Developmental delays are common in infancy and childhood. Expected symptoms include speech delays, motor delays, and hypotonia (lack of muscle tone), also known as floppy baby syndrome. Individuals with XXXY syndrome exhibit cognitive and behavioral problems. [2]

Patients typically show altered adaptive behavior, which is the ability of an individual to demonstrate essential living skills, including: social skills, community living, safety, functional use of academic skills and self-care. People with XXXY syndrome were found to score significantly less in the domains of daily living skills and communication compared to XXYY, and XXY individuals. [3] This means that they typically demonstrate little ability in the domains of self-care, social skills, safety, application of academic skills, and responsibility. [3]

Individuals with this syndrome also experience emotional symptoms such as anxiety symptoms, obsessive-compulsive behaviors, behavioral dysregulational and emotional immaturity. [3] People with this syndrome typically have an IQ in the range of 40-60, where the average IQ range is 95-110. [5] [7] They also experience language-based learning disabilities that can affect their communication with others. [4] Those with XXXY syndrome tend to display less externalizing and internalizing behaviors compared to those with 48,XXYY syndrome, which may have a positive effect on their social functioning. [8] These individuals may also have increased vulnerability for autistic features. [8] Changes in testosterone as well as androgen deficits may contribute to these individuals’ social behaviors that put them at increased risk for autistic features. [8]

Cause

The cause of 48,XXXY can be from non-disjunction in the paternal sperm or non-disjunction in the maternal oocyte. [3] The most likely scenario for the existence of this aneuploidy is that each party (maternal and paternal) equally contributed to it, by the egg giving an XX and the sperm giving an XY. [3]

In the case where the sperm is the genetic cause of 48,XXXY syndrome, the sperm would have to contain two X chromosomes and one Y chromosome. This would be caused by two nondisjunction events in spermatogenesis, both meiosis I and meiosis II. The duplicated X chromosome in the sperm would have to fail to separate in both meiosis I and meiosis II for a sperm as well as the X and Y chromosomes would have to be in the same sperm. Then the XXY sperm would fertilize a normal oocyte to make a XXXY zygote. [5]

In the case where the oocyte is the genetic cause of 48,XXXY syndrome the oocyte would contain three X chromosome. This would be caused by two nondisjunction events during oogenesis. In meiosis I both sets of duplicated X chromosomes would have to be not separated. Then in meiosis II one set of X chromosomes would have to not separate and the other set would separate resulting in one oocyte with three X chromosomes. A normal sperm containing a Y chromosome would have to fertilize the XXX oocyte to make a XXXY zygote. [5]

Mechanism

The additional X chromosomes that are characteristic of this condition are associated with an androgen deficiency. [2] This causes reduced or absent feedback inhibition of the pituitary gland, by elevating the gonadotropin levels. [2]

Diagnosis

Diagnosis of 48,XXXY is usually done by a standard karyotype, a chromosomal analysis in which a full set of chromosomes can be seen for an individual. [3]

Another way to diagnosis 48,XXXY is by chromosomal microarray showing the presence of extra X chromosomes. [3] Chromosomal microarray (CMA) is used to detect extra or missing chromosomal segments or whole chromosomes. CMA uses microchip-based testing to analyze many pieces of DNA. Males with 48,XXXY are diagnosed anywhere from before birth to adulthood as a result of the range in the severity of symptoms. [3] The age range at diagnosis is likely due to the fact that XXXY is a rare syndrome, and does not cause as extreme phenotypes as other variants of Klinefelter syndrome (such as XXXXY). [3]

Diagnostic testing could also be done via blood samples. Elevated levels of follicle stimulating hormone, luteinizing hormone, and low levels of testosterone can be indicative of this syndrome. [5]

Management

Treatment

Treatments exist for the various symptoms associated with XXXY syndrome. Testosterone therapy, which is giving affected individuals doses of testosterone on a regular basis, has been shown to improve some physical and psychological symptoms. [3] However, this therapy has also been associated with negative side effects: worsening of behavior, and osteoporosis. [3] Not all individuals are applicable for testosterone therapy, as the best results are often achieved when dosage begins at the initiation of puberty, and these individuals are often diagnosed at a later age, or not at all. [3] Testosterone therapy has been shown to have no positive effect on fertility. [2]

Consideration of the psychological phenotype of individuals with XXXY should be taken into account when treating these patients, because these traits affect compliance with treatments. [3] When caught early, Taurodontism can be treated with a root canal and is often successful. [2] Appropriate planning to avoid Taurodontism is possible, but this syndrome must be diagnosed early, which is not common. [2] Taurodontism can often be detected as a symptom of XXXY syndrome before other characteristics develop, and can be an early indicator for it. Surgical treatments to correct joint problems, such as hip dysplasia are common, and are often successful alongside physiotherapy. [6]

Those with XXXY syndrome can also attend speech therapy. [5] This form of therapy helps patients to understand and produce more complex language. [5] Those with XXXY syndrome tend to experience more severe speech delays, so this form of treatment can be very beneficial to them, and can help them to communicate better with other people. [5]

Since hypotonia is common in those with this syndrome, physical therapy can also be helpful. [5] This form of therapy may help these individuals develop muscle tone, and increase balance and coordination. [5]

Quality of life

In mild cases, individuals with XXXY syndrome may lead a relatively good life. These individuals may face difficulties in communicating with others due to their language-based deficits. These deficits may make forming bonds with others difficult, but fulfilling relationships with others are still achievable. Those with higher scores in adaptive functioning are likely to have higher quality of life because they can be independent. [3]

Genetic counselling

As the syndrome is due to a chromosomal non-disjunction event, the recurrence risk is not high compared to the general population. [5] There has been no evidence found that indicates non-disjunction occurs more often in a particular family. [5]

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">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">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 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.

<span class="mw-page-title-main">Male reproductive system</span> Reproductive system of the human male

The male reproductive system consists of a number of sex organs that play a role in the process of human reproduction. These organs are located on the outside of the body, and within the pelvis.

<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 congenital intersex condition in which an individual with a 46,XX karyotype develops a male phenotype. 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.

<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.

<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. As the presence of a Y chromosome denotes male sex, people with Klinefelter syndrome are genetically male. 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.

A tetrasomy is a form of aneuploidy with the presence of four copies, instead of the normal two, of a particular chromosome.

Sex chromosome anomalies belong to a group of genetic conditions that are caused or affected by the loss, damage or addition of one or both sex chromosomes.

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.

<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">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

  1. ↑ "XXXY syndrome". The Genetic and Rare Diseases Information Center (GARD). NIH. 10 August 2016. Retrieved 19 March 2019.
  2. 1 2 3 4 5 6 7 8 9 10 11 Joseph, Michael (2008-05-01). "Endodontic treatment in three taurodontic teeth associated with 48,XXXY Klinefelter syndrome: a review and case report". Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontology. 105 (5): 670–677. doi:10.1016/j.tripleo.2007.11.015. PMID   18442747.
  3. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 Tartaglia, Nicole; Ayari, Natalie; Howell, Susan; D’Epagnier, Cheryl; Zeitler, Philip (2011-06-01). "48,XXYY, 48,XXXY and 49,XXXXY syndromes: not just variants of Klinefelter syndrome". Acta Paediatrica. 100 (6): 851–860. doi:10.1111/j.1651-2227.2011.02235.x. ISSN   1651-2227. PMC   3314712 . PMID   21342258.
  4. 1 2 3 Skakkebæk, N.E.; Meyts, E. Rajpert-De; Main, K.M. (2001-05-01). "Testicular dysgenesis syndrome: an increasingly common developmental disorder with environmental aspects: Opinion". Human Reproduction. 16 (5): 972–978. doi: 10.1093/humrep/16.5.972 . ISSN   0268-1161. PMID   11331648.
  5. 1 2 3 4 5 6 7 8 9 10 11 12 13 Visootsak, Jeannie; Graham, John M. (2006-10-24). "Klinefelter syndrome and other sex chromosomal aneuploidies". Orphanet Journal of Rare Diseases. 1: 42. doi: 10.1186/1750-1172-1-42 . ISSN   1750-1172. PMC   1634840 . PMID   17062147.
  6. 1 2 Simşek, P. O.; Utine, G. E.; Alikaşifoğlu, A.; Alanay, Y.; Boduroğlu, K.; Kandemir, N. (2009). "Rare sex chromosome aneuploidies: 49,XXXXY and 48,XXXY syndromes". The Turkish Journal of Pediatrics. 51 (3): 294–297. ISSN   0041-4301. PMID   19817277.
  7. ↑ "APA PsycNet".
  8. 1 2 3 [ citation needed ]

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