49,XXXXY syndrome is an extremely rare aneuploidicsex chromosomal abnormality. It occurs in approximately 1 out of 85,000 to 100,000 males.[1][2][3] This syndrome is the result of maternal non-disjunction during both meiosis I and II.[4] It was first diagnosed in 1960 and was coined Fraccaro syndrome after the researcher.[2]
The symptoms of 49,XXXXY are slightly similar to those of Klinefelter syndrome and 48,XXXY, but they are usually much more severe. Aneuploidy is often fatal, but there is "X-inactivation", where the effect of the additional gene dosage due to the presence of extra X chromosomes is greatly reduced.[5]
Much like Down syndrome, the mental effects of 49,XXXXY syndrome vary. Impaired speech and maladaptive behavioral problems are typical.[9] One study looked at males that were diagnosed with 48,XXYY, 48,XXXY and 49,XXXXY. They found that males with 48,XXXY and 49,XXXXY function at a much lower cognitive level than males their age. These males also tend to exhibit more immature behavior for their chronological age; increased aggressive tendencies were also cited in this study.[9]
A 2020 study found that boys with 49,XXXXY have heightened rates of internalizing behavior and anxiety, beginning as early as preschool.[10] Tests using the Social Responsiveness Scale-2 (SRS-2) found that while those with the condition generally showed more signs of social impairment, there was minimal effect on their social awareness.[10]
As its name indicates, a person with the syndrome has one Y chromosome and four X chromosomes on the 23rd pair, thus having forty-nine chromosomes rather than the normal forty-six. As with most categories of aneuploidy disorders, 49,XXXXY syndrome is often accompanied by intellectual disability. It can be considered a form or variant of Klinefelter syndrome (47,XXY).[11] Individuals with this syndrome are typically mosaic, being 49,XXXXY/48, XXXX.[4]
It is genetic but not hereditary, meaning that while the genes of the parents cause the syndrome, there is a small chance of more than one child having the syndrome. The probability of inheriting the disease is about one percent.[5]
While there is no treatment to correct the genetic abnormality of this syndrome, there is the potential to treat the symptoms. As a result of infertility, one man from Iran used artificial reproductive methods.[4] An infant in Iran diagnosed with 49,XXXXY syndrome was born with patent ductus arteriosus, which was corrected with surgery, and other complications that were managed with replacement therapy.[4]
The administration of testosterone therapy has been shown to improve motor skills, speech, and nonverbal IQ in males with 49,XXXXY.[13]
^ abcdeHadipour, Fatemeh; Shafeghati, Yousef; Bagherizadeh, Eiman; Behjati, Farkhondeh; Hadipour, Zahra (2013). "Fraccaro syndrome: report of two Iranian cases: an infant and an adult in a family". Acta Medica Iranica. 51 (12): 907–909. ISSN1735-9694. PMID24442548.
^Sprouse, Courtney; Tosi, Laura; Stapleton, Emily; Gropman, Andrea L.; Mitchell, Francie L.; Peret, Rick; Sadeghin, Teresa; Haskell, Kathryn; Samango-Sprouse, Carole A. (2013). "Musculoskeletal anomalies in a large cohort of boys with 49, XXXXY". American Journal of Medical Genetics. 163 (1): 44–49. doi:10.1002/ajmg.c.31354. PMID23359596. S2CID40989726.
^ abVisootsak J, Rosner B, Dykens E, Tartaglia N, Graham JM (June 2007). "Behavioral phenotype of sex chromosome aneuploidies: 48,XXYY, 48,XXXY, and 49,XXXXY". Am. J. Med. Genet. A. 143A (11): 1198–203. doi:10.1002/ajmg.a.31746. PMID17497714. S2CID25732790.
^ abLasutschinkow, Patricia C.; Gropman, Andrea L.; Porter, Grace F.; Sadeghin, Teresa; Samango-Sprouse, Carole A. (2020-02-21). "Behavioral phenotype of 49,XXXXY syndrome: Presence of anxiety-related symptoms and intact social awareness". American Journal of Medical Genetics. 182 (5): 974–986. doi:10.1002/ajmg.a.61507. PMID32083381. S2CID211230717 – via Wiley Online Database.
^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. ISBN0-7216-0187-1.
^Tosi, Laura; Mitchell, Francie; Porter, Grace F.; Ruland, Leigh; Gropman, Andrea; Lasutschinkow, Patricia C.; Tran, Selena L.; Rajah, Elmer N.; Gillies, Austin P.; Hendrie, Patricia; Peret, Rick; Sadeghin, Teresa; Samango-Sprouse, Carole A. (2020-04-03). "Musculoskeletal abnormalities in a large international cohort of boys with 49,XXXXY". American Journal of Medical Genetics. 185 (12): 3531–3540. doi:10.1002/ajmg.a.61578. PMID32243688. S2CID214785617 – via Wiley Online Database.