Tetrasomy X
Tetrasomy X | |
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Other names | 48,XXXX |
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Karyotype of tetrasomy X | |
Specialty | Medical genetics ![]() |
Symptoms | Intellectual disability, facial dysmorphology, heart defects, skeletal anomalies, tall stature |
Usual onset | Conception |
Duration | Lifelong |
Causes | Nondisjunction |
Diagnostic method | Karyotype |
Differential diagnosis | Trisomy X, pentasomy X, Down syndrome |
Tetrasomy X, also known as 48,XXXX, is a
The disorder has a wide range of symptoms, with phenotypes (presentations) ranging from slight to severe. It is suspected to be underdiagnosed, as are other sex chromosome disorders. Life outcomes vary; some women have had education, employment, and children, while others have remained dependent into adulthood. Life expectancy does not appear to be substantially reduced. Tetrasomy X has phenotypic overlap with a number of more common disorders, such as trisomy X and Down syndrome, and diagnosis is usually unclear prior to chromosomal testing.
Tetrasomy X is generally not inherited, but rather occurs via a random event called nondisjunction during gamete or zygote development. The formal term for the karyotype[note 1] observed in tetrasomy X is 48,XXXX, as the condition is typified by a 48-chromosome complement rather than the 46 chromosomes observed in normal human development.
Presentation
Tetrasomy X has a variable presentation with a spectrum of severity, and lacks obvious defining clinical abnormalities that can lead to a diagnosis in the absence of testing.[2] Recognizable characteristics include increased height and mild intellectual disability; the average adult height in tetrasomy X is 169 cm (5 ft 6+1⁄2 in)[2] compared with a reference height of around 162 cm (5 ft 4 in) for women in the Anglosphere,[3][4] while a review of the first 27 women to be diagnosed with tetrasomy X found IQs ranging from 30 to 101 with a mean of 62.[5] Although some degree of intellectual disability is traditionally characteristic, two medically reported cases were of normal intelligence,[6] and patient organizations report members who are only afflicted by specific learning disabilities such as dyslexia.[7] Speech and language delays may be associated with tetrasomy X, although the matter is unclear; some reports describe speech and language abilities in line with overall intelligence,[2] while others describe problems independent of intelligence, in particular with subjects who have normal intelligence but significant language delays.[6][8]
A number of facial and musculoskeletal anomalies are common to all
Heart defects of various types have been associated with the syndrome, albeit at unclear prevalence. A patient organization reports approximately one-third of cases in its membership had congenital heart defects, a larger proportion than reported in the medical literature.
The psychological and behavioural phenotype of tetrasomy X is understudied. Some reports describe girls and women with tetrasomy X as generally placid and pleasant, while others report emotional lability and inappropriate behaviour.[2] Family background and environment has a significant impact on behaviour, and cases with severe behavioural dysfunction frequently have similarly dysfunctional unaffected relatives. Expressive language delays and executive dysfunction are common heralds of behavioural issues, due to the difficulties they cause for educational, vocational, and social functioning.[6] In both men and women X-chromosome polysomy is known to be associated with psychosis,[21] and a case is known of a girl with tetrasomy X and childhood-onset schizophrenia.[22] Parent reports describe children and young adults who are generally pleasant and affectionate yet shy, and have issues relating to temper tantrums, mood swings, and frustration at an inability to communicate.[7]
Tetrasomy X can interfere with
Causes
![](http://upload.wikimedia.org/wikipedia/commons/thumb/8/8d/XXXX_syndrome.svg/220px-XXXX_syndrome.svg.png)
Tetrasomy X, like other
Nondisjunction is related to advanced maternal age.[31] In common aneuploidies such as Down syndrome, the relationship with maternal age is extensively studied.[32] In Klinefelter syndrome, the most common and most studied sex chromosome aneuploidy, incidence increases substantially as maternal age rises.[33] Less is understood about the role of maternal age in sex chromosome tetrasomy and pentasomy conditions, primarily due to their rarity, and no clear relationship has been established.[5][34]
Tetrasomy X is generally a random occurrence and does not recur in the same family. In rare cases, it may be related to a mother having trisomy X, mosaic or otherwise. It is not caused by environmental factors.[7]
Diagnosis
Chromosome aneuploidies such as tetrasomy X are diagnosed via karyotype,[35] the process in which chromosomes are tested from blood, bone marrow, amniotic fluid, or placental cells.[36] Due to significant differential diagnosis potential, diagnosis cannot be made on the basis of phenotype alone.[2]
Differential diagnosis
Tetrasomy X has many possibilities for differential diagnosis, with multiple other conditions overlapping with the phenotype. One differential diagnosis is
Pentasomy X, a karyotype of five X chromosomes, is another major differential diagnosis. The phenotype of pentasomy X is similar but on average more severe. Intellectual disability is more severe, with an average IQ of 50, and pubertal delay or incomplete puberty appears more common.[2] Unlike other X-chromosome polysomies, pentasomy X is associated with short stature.[10] Similarly, pentasomy X is commonly associated with findings that are infrequent in tetrasomy X such as microcephaly and intrauterine growth restriction.[13] Cases of 48,XXXX/49,XXXXX mosaicism have been reported, and are often categorized as cases of pentasomy X.[41] More complex mosaics have been reported, such as 47,XXX/48,XXXX/49,XXXXX[17] and 45,X0/46,XX/47,XXX/48,XXXX/49,XXXXX.[42]
An additional differential diagnosis in some cases is Down syndrome. Some cases of tetrasomy X have been described as having "a false air of trisomy 21" (the underlying chromosomal aneuploidy in Down's), and karyotyping resulting in a diagnosis of tetrasomy X has been performed due to suspicion of Down syndrome.[37][43] However, this is only a differential diagnosis for a subset of cases, while others have more normal phenotypes or abnormalities inconsistent with the Down's profile.[37] The matter is complicated by the observation that a number of women with X chromosome polysomy, including tetrasomy X, have had children with Down syndrome.[2][44]
Prognosis
The long-term prognosis for tetrasomy X appears generally good. While life expectancy is unclear, patients have been diagnosed in their 50s and 60s, and long-term follow-up of individual cases shows healthy aging with good physical health.[5][45] Some women live fully independent lives, while others require more persistent support from parents and caregivers, consistent with other intellectual disability syndromes of comparable severity.[7] Many are able to work part-time, and some full-time; some young women attend tertiary education, mostly vocational.[46] Girls and women with tetrasomy X and good outcomes are typified by supportive family environments and strong personal advocacy for their success; "[t]he children have been exposed to many varied activities and experiences and are praised for their strengths, while their limitations and delays are minimised".[2] Adolescents should undergo screening for ovarian insufficiency, as hormone replacement therapy may be required to mitigate the risk of osteoporosis.
Epidemiology
Tetrasomy X is estimated to occur in approximately 1 in 50,000 females, with a prevalence of less than 1 in one million people.[47][48] Considering the variable phenotype, tetrasomy X support organizations and researchers think it likely there are many cases that have not come to medical attention.[7] This is common to all sex chromosome aneuploidies, which have very low diagnosis rates compared to their overall population prevalence.[10] Overall, sex chromosome tetrasomy and pentasomy disorders occur in 1 in 18,000 to 1 in 100,000 male live births, and are somewhat rarer in females.[2][49]
Tetrasomy X only occurs in females, as the Y chromosome is in most cases necessary for male sexual development.[50][note 3]
History
Tetrasomy X was first recorded in 1961 in two intellectually disabled women residing in an institution.
Much of the medical literature for tetrasomy X dates to the 1960s and 1970s, an era of particular interest in and research on sex chromosome aneuploidy.[7] Early reports were frequently discovered during chromosome screenings in institutions for the intellectually disabled.[5][60][61] The early preference for diagnosis of sex chromosome aneuploidy in selected samples, such as institution residents and prisoners, led to a biased perspective on the conditions that painted an unduly negative portrait of their phenotypes and prognoses. Further research on sex chromosome aneuploidy via unselected samples such as newborn screening allowed for major conditions such as XYY syndrome, Klinefelter syndrome, and trisomy X to be re-defined by more representative phenotypes; however, rarer conditions such as tetrasomy X were not ascertained in any such studies, and therefore the medical literature continues to describe cases that were diagnosed due to developmental or behavioural issues.[2] Aspects of the early studies remain accepted; a 1969 proposal that each supernumerary X chromosome reduces IQ by an average of 15 points[62] is still used as a rule of thumb.[2][7][63]
Sex chromosome tetrasomy and pentasomy conditions have consistently received little attention compared to the more common trisomy conditions. Research into conditions such as tetrasomy X has been stymied by biased samples, outdated information, and a lack of publications above the case report level.
Diagnosis of sex chromosome aneuploidies is increasing,[16] as is the number of supports available for families.[65] The rarity of and variation in tetrasomy X limits the amount of specific support available, but major chromosome disorder organizations serve the condition and have members who are or are associates of people with it.[46]
Notes
- ^ 'Karyotype' as a term has multiple meanings, all of which are used here. It may refer to a person's chromosome complement, to the test used to discern said chromosome complement, or to an image of chromosomes ascertained via such a test.[1]
- ^ Aneuploidy is the presence of too many or too few chromosomes in a cell.[9]
- ^ Male phenotypes, innate or induced, with forms of X chromosome polysomy that are usually phenotypically female do occur. For trisomy X, a trans man and several men with sex reversal have been recorded.[51][52][53]
References
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- ^ US Dept. of Health and Human Services, et al. (August 2016). "Anthropometric reference data for children and adults: United States, 2011–2014" (PDF). National Health Statistics Reports. 11. Archived (PDF) from the original on 2 February 2017. Retrieved 23 March 2021.
- ^ "Australian health survey: first results". Australian Bureau of Statistics. 29 October 2012. Archived from the original on 20 January 2017. Retrieved 23 March 2021.
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- ^ a b c d e f g h i j k l m n o Rooman R, Hultén M (2005). "Tetrasomy X" (PDF). Unique. Archived (PDF) from the original on 18 March 2021.
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- ^ a b Xiong WY, Jiang ZY, Zou CC (January 2014). "Tetrasomy X in a child with multiple abnormalities: case report and literature review from China". Hong Kong Journal of Paediatrics. 19 (1): 37–40.
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- ^ Bilge S, Mert GG, Özcan N, Özcanyüz D (September 2020). "Tetrasomy X, a rare cause of epilepsy and behavior disorder". Acta Scientific Neurology. 3 (9): 56–58.
- ^ AXYS, Berry Kravis E (December 2020). "Seizures and tremor in people with X & Y chromosome variations" (PDF). AXYS: Association for X and Y Chromosome Variations. Retrieved 26 March 2021.
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- ^ Arbelaez HEM, Aldana CTS, Bravo NCC, Ospina SY, Mendoza DJF (May 2010). "Análisis clínico y molecular de una pacientecon pentasomia del cromosoma X". Acta Biológica Colombiana (in Spanish). 15 (2): 61–72.
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- ^ O'Connor C (2008). "Chromosomal abnormalities: aneuploidies". Nature Education. 1 (1): 172. Archived from the original on 3 November 2020.
- ^ Edens Hurst AC, Zieve D, Conaway B (2 April 2021). "Karyotyping". MedlinePlus. Retrieved 9 April 2021.
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- ^ Ayara N, Berge A, Howell S, Tartaglia N. "Orphanet: Tetrasomía X". Orphanet. Retrieved 24 March 2024.
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- ^ "Tetrasomy/Pentasomy X Support Group". National Organization for Rare Disorders. Archived from the original on 24 April 2016. Retrieved 10 April 2021.
- ^ Auchmutey P (2018). "Extraordinary care". Emory Health Digest. Archived from the original on 6 August 2020. Retrieved 26 March 2021.
External links
Media related to Tetrasomy X at Wikimedia Commons