49,XXXXY syndrome | |
---|---|
Other names | Fraccaro syndrome |
A 19-year-old man with XXXXY syndrome and prognathism | |
Specialty | Medical genetics |
Usual onset | Prenatal |
Duration | Lifelong |
Causes | Cellular nondisjunction during meiosis |
Diagnostic method | Karyotype |
Frequency | 1 in 85,000 to 100,000 |
49,XXXXY syndrome is an extremely rare aneuploidic sex 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]
Those with 49,XXXXY syndrome tend to exhibit infantile secondary sex characteristics with sterility in adulthood.[5]
Males with 49,XXXXY tend to have numerous skeletal anomalies. These skeletal anomalies include:[7]
The effects also include:
49,XXXXY may also be associated with increased rates of primary immunodeficiency.[8]
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]
49,XXXXY can be clinically diagnosed through karyotyping.[12] Facial dysmorphia and other somatic abnormalities may be reason to have the genetic testing done.[4]
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]