XXXXY syndrome

Signs and symptoms

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, although the effect of the additional gene dosage is greatly reduced due to lyonization, leaving 3 Barr bodies.

Reproductive

Those with 49,XXXXY syndrome tend to exhibit infantile secondary sex characteristics with sterility in adulthood.

• Hypoplastic genitalia
• Absent or delayed puberty

Physical

Males with 49,XXXXY tend to have numerous skeletal anomalies. These skeletal anomalies include:

• Genu valgum
• Pes cavus
• Fifth finger clinodactyly

The effects also include:

• Cleft palate
• Club feet
• Respiratory conditions
• Short or/and broad neck
• Low birth weight
• Hyperextensible joints
• Short stature
• Narrow shoulders
• Coarse features in older age
• Hypertelorism
• Epicanthal folds
• Prognathism
• Gynecomastia (rare)
• Muscular hypotonia
• Cryptorchidism
• Congenital heart defects
• A very round face in infancy

49,XXXXY may also be associated with increased rates of primary immunodeficiency.

Cognitive and developmental

Much like Down syndrome, the mental effects of 49,XXXXY syndrome vary. Impaired speech and maladaptive behavioral problems are typical. 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.

A 2020 study found that boys with 49,XXXXY have heightened rates of internalizing behavior and anxiety, beginning as early as preschool. 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.

Pathophysiology

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). Individuals with this syndrome are typically mosaic, being 49,XXXXY/48, XXXX.

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.

Diagnosis

49,XXXXY can be clinically diagnosed through karyotyping. Facial dysmorphia and other somatic abnormalities may be reason to have the genetic testing done.

Treatment

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. 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.

The administration of testosterone therapy has been shown to improve motor skills, speech, and nonverbal IQ in males with 49,XXXXY.

References

References

1. (2006). "Klinefelter syndrome and other sex chromosomal aneuploidies". Orphanet J Rare Dis.
2. (1960-10-22). "A child with 49 chromosomes". Lancet.
3. (March 2015). "Neonatal diagnosis of 49, XXXXY syndrome". Iranian Journal of Reproductive Medicine.
4. (2020-07-29). "Sexual and developmental aspects of 49, XXXXY Syndrome: A case report". Andrologia.
5. (2013). "Musculoskeletal anomalies in a large cohort of boys with 49, XXXXY". American Journal of Medical Genetics.
6. (2013-01-23). "Immunodeficiency in patients with 49,XXXXY chromosomal variation". American Journal of Medical Genetics.
7. (June 2007). "Behavioral phenotype of sex chromosome aneuploidies: 48,XXYY, 48,XXXY, and 49,XXXXY". Am. J. Med. Genet. A.
8. (2020-02-21). "Behavioral phenotype of 49,XXXXY syndrome: Presence of anxiety-related symptoms and intact social awareness". American Journal of Medical Genetics.
9. (2005). "Robbins and Cotran pathologic basis of disease". Elsevier Saunders.
10. [http://www.webspawner.com/users/49xxxxysyndrome/ Webspawner.com article on 49,XXXXY syndrome] {{Webarchive. link. (2008-09-14 . Retrieved 26 March 2008.)
11. (2013). "Brain morphological abnormalities in 49,XXXXY syndrome: A pediatric magnetic resonance imaging study". NeuroImage: Clinical.
12. (2013). "Fraccaro syndrome: report of two Iranian cases: an infant and an adult in a family". Acta Medica Iranica.
13. (2020-04-03). "Musculoskeletal abnormalities in a large international cohort of boys with 49,XXXXY". American Journal of Medical Genetics.