XXXY syndrome

XXXY syndrome is a genetic condition marked by an abnormal number of sex chromosomes, where individuals have two additional X chromosomes. Typically, people possess two sex chromosomes: either an X and a Y or two X chromosomes. The presence of a Y chromosome with a functional SRY gene triggers the expression of genes responsible for male characteristics.

Consequently, XXXY syndrome affects only males. The extra two X chromosomes in males with XXXY syndrome result in a total of 48 chromosomes, rather than the usual 46. Hence, XXXY syndrome is often called 48,XXXY.

This syndrome is associated with a wide range of symptoms, including cognitive and behavioral issues, taurodontism, and infertility. It generally arises from a new mutation in one of the parent's gametes, as affected individuals are typically infertile. XXXY syndrome is estimated to occur in one out of every 50,000 male births.

Signs and symptoms

The symptoms of 48,XXXY syndrome are akin to those of Klinefelter syndrome, although they are usually more severe in 48,XXXY syndrome. Similar to Klinefelter syndrome, the presence of extra X chromosomes impacts the male reproductive system, can lead to physical abnormalities, and may affect cognitive development. Comparing 47,XXY with 48,XXXY, there is a higher risk of congenital malformations and more medical issues in those with 48,XXXY.

Reproductive

Individuals with XXXY syndrome may experience testicular dysgenesis and hypergonadotrophic hypogonadism. Testicular dysgenesis involves incomplete or complete loss of spermatogenesis, leading to very low or absent sperm production, resulting in infertility. Hypergonadotrophic hypogonadism is a condition where the testicular function is reduced, potentially causing low levels of sex steroids like testosterone.

Physical

Males with 48,XXXY may have average or tall stature, which becomes more noticeable in adulthood. Facial dysmorphism is common, including increased distance between the eyes (hypertelorism), skin folds of the upper eyelid (epicanthal folds), up-slanting eyelid openings (palpebral fissures), and hooded eyelids. Other features include the fifth finger bending inward towards the fourth finger (clinodactyly), short nail beds, flat feet, double jointedness (hyperextensibility), and prominent elbows with cubitus varus, where the arm is closer to the body. Musculoskeletal features may include congenital elbow dislocation and limited inward foot rolling while walking and upon landing. Micropenis is another common symptom.

Those with XXXY are also prone to taurodontism, which often appears early and can be an early sign of XXY syndrome. They are also susceptible to hip dysplasia and other joint abnormalities. Symptoms vary due to differing androgen deficiencies and change with age. Prepubescent boys with XXXY syndrome may not differ in appearance from children without the syndrome, likely because androgen levels are similar among prepubescent boys, but differences arise during puberty. Those with XXXY syndrome may also experience a feminine distribution of body fat, and gynecomastia may be present. Tall stature is more likely to appear in adolescence when androgen levels begin to differ between those with and without XXXY syndrome.

Cognitive and developmental

Neurological effects are thought 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 one with Klinefelter syndrome. Developmental delays are common in infancy and childhood, including speech delays, motor delays, and hypotonia (lack of muscle tone), also known as floppy baby syndrome. Individuals with XXXY syndrome show cognitive and behavioral problems.

Patients typically exhibit altered adaptive behavior, which is the ability to demonstrate essential living skills, including social skills, community living, safety, functional use of academic skills, and self-care. People with XXXY syndrome score significantly lower in daily living skills and communication domains compared to XXYY and XXY individuals, indicating limited abilities in self-care, social skills, safety, academic skills application, and responsibility.

Individuals with this syndrome also experience emotional symptoms such as anxiety, obsessive-compulsive behaviors, behavioral dysregulation, and emotional immaturity. Typically, they have an IQ range of 40–60, whereas the average IQ range is 95–110. They also face language-based learning disabilities affecting their communication. Those with XXXY syndrome tend to exhibit fewer externalizing and internalizing behaviors than those with 48,XXYY syndrome, which may positively affect their social functioning. These individuals may also be more vulnerable to autistic features. Changes in testosterone and androgen deficits may influence their social behaviors, increasing the risk of autistic features.

Cause

The cause of 48,XXXY can result from non-disjunction in the paternal sperm or the maternal oocyte. The most likely scenario for this aneuploidy is equal contribution from each parent, with the egg providing an XX and the sperm an XY.

If the sperm is the genetic cause of 48,XXXY syndrome, it would contain two X chromosomes and one Y chromosome due to two nondisjunction events during spermatogenesis, in both meiosis I and II. The duplicated X chromosome in the sperm would fail to separate in both meiosis I and II, resulting in a sperm containing both X and Y chromosomes. This XXY sperm would fertilize a normal oocyte to create a XXXY zygote.

If the oocyte is the genetic cause of 48,XXXY syndrome, it would have three X chromosomes due to two nondisjunction events during oogenesis. In meiosis I, both sets of duplicated X chromosomes would not separate. Then, in meiosis II, one set of X chromosomes would not separate, while the other would, resulting in an oocyte with three X chromosomes. A normal sperm with a Y chromosome would fertilize the XXX oocyte to form a XXXY zygote.

Mechanism

The additional X chromosomes characteristic of this condition are linked to an androgen deficiency, leading to reduced or absent feedback inhibition of the pituitary gland and elevated gonadotropin levels.

Diagnosis

48,XXXY is usually diagnosed through a standard karyotype, a chromosomal analysis showing an individual's full set of chromosomes.

Another diagnostic method is chromosomal microarray to detect extra X chromosomes. Chromosomal microarray (CMA) identifies extra or missing chromosomal segments or whole chromosomes using microchip-based DNA analysis. Males with 48,XXXY are diagnosed from before birth to adulthood, depending on symptom severity. The age range at diagnosis is likely due to the rarity of XXXY syndrome and its less extreme phenotypes compared to other Klinefelter syndrome variants (such as XXXXY).

Diagnostic testing can also be performed via blood samples. Elevated follicle stimulating hormone, luteinizing hormone levels, and low testosterone levels can indicate this syndrome.

Management

Treatment

Various treatments exist for the symptoms of XXXY syndrome. Testosterone therapy, involving regular testosterone doses, has been shown to improve some physical and psychological symptoms. However, it may have negative side effects, such as worsening behavior and osteoporosis. Not all individuals are suitable for testosterone therapy, as the best results occur when treatment begins at puberty onset, and diagnosis often occurs later or not at all. Testosterone therapy does not improve fertility.

The psychological profile of individuals with XXXY should be considered in treatment, as these traits affect treatment compliance. Early detection of Taurodontism allows for successful root canal treatment. Planning to prevent Taurodontism is possible, but early diagnosis of this syndrome is uncommon. Taurodontism can be an early indicator of XXXY syndrome before other characteristics develop. Surgical treatments for joint problems, like hip dysplasia, are common and often successful with physiotherapy.

Individuals with XXXY syndrome can also attend speech therapy to help them understand and use more complex language. This therapy is beneficial for those with severe speech delays, improving communication with others.

Since hypotonia is common in this syndrome, physical therapy can help develop muscle tone, balance, and coordination.

Quality of life

In mild cases, individuals with XXXY syndrome may lead relatively good lives. They may face communication difficulties due to language-based deficits, making relationship-building challenging, but fulfilling relationships are still achievable. Those with higher adaptive functioning scores are likely to have a better quality of life due to their independence.

Genetic counselling

As the syndrome results from a chromosomal non-disjunction event, the recurrence risk is not significantly higher than in the general population. There is no evidence suggesting non-disjunction occurs more frequently in specific families. XXXY syndrome