XXXXY syndrome is characterised by the presence of three extra X chromosomes in males also known as 49,XXXXY.
XXXXY syndrome also known as Fraccaro syndrome is an extremely rare sex chromosomal abnormality occurring in approximately 1 out of 85,000 to 100,000 males. A male typically has 46 chromosomes including 2 sex chromosomes X and Y which determine whether a person will develop male or female sex characteristics. Females typically have two X chromosomes (46XX), and males have one X chromosome and one Y chromosome (46XY) in each cell. XXXXY syndrome is characterised by the presence of three extra X chromosomes in males (49,XXXXY). It is less common than the other chromosomal disorders and although it is sometimes referred to as a variant of Klinefelter Syndrome it differs from Klinefelter in many ways and is more severe.
Who is affected
XXXXY syndrome is a rare chromosomal disorder present at birth and affects only males. This syndrome is less common than other chromosomal disorders where boys have more X chromosomes than expected.
Causes
49,XXXXY syndrome is caused by a random error in cell division in the egg cells of the mother. During normal egg formation the chromosomes separate into separate eggs. If they don’t separate correctly one egg ultimately retains all the X chromosomes and if an egg cell containing four X chromosomes is fertilized by a typical male the resulting egg cell will be affected. The underlying reason for random errors in cell division is not known. XXXXY syndrome is not inherited and there isn’t anything someone can do or not do before, during or after pregnancy to cause this syndrome to happen. The chances of someone who has had a child with XXXXY having another pregnancy with the disorder isn’t any higher than for the general population.
Signs and symptoms
Characteristics of 49,XXXXY syndrome can vary widely between individuals but may include learning difficulties or intellectual disability, which often accompany the condition. They may suffer specific speech difficulties, although understanding is usually better than expressive language and visual skills are usually more advanced than expression. They often have a subtle intellectual deficit in childhood but progressive (moderate to severe) deterioration with age (IQ varying between 70 and 20) which is associated with a major delay in language development.
Affected people typically have delayed growth (often seen in utero, before birth). They might start out relatively small and thin with a variable growth pattern. Slow growth with delayed bone age is considered typical although the child usually catches up later in life. They also experience gross motor delay and co-ordination difficulties and another commonality in an individual with the condition is low muscle tone (hypotonia), often with reduced muscle strength and motor skill difficulties.
Additionally individuals also have under-developed sex organs and or undescended testis at birth. Development is atypical during puberty with small testicles and low production of sex hormones (testosterone). In the individual with 49,XXXXY the hormonal function of the testes can vary from nearly normal to severely deficient. Most start puberty naturally but don’t produce enough testosterone to complete puberty causing infertility.
Other features that may occur are a high rate of respiratory infection, in childhood many boys have severe respiratory infection or asthma and these may continue into adulthood. Most boys with the syndrome also have distinctive facial features with wide set eyes, low nasal bridge and a small chin.
Individuals with XXXXY syndrome have a 15-20percent chance of having a heart condition and suffer from a variety of birth defects that may affect the bones, brain and/or kidneys.
Behavioural problems can also arise. They tend to start out with a gentle and pleasant nature until the toddler years as frustration at their inability to communicate starts to show. Many boys have temper tantrums and exhibit a low frustration tolerance and resistance to changes in routine.
Despite their sociability an individual is often sensitive to the environment and usually needs considerable social support.
Diagnosis
Testing is often requested by a doctor prenatally due to slow intra-uterine growth, which is quite common. Diagnosis of the disorder is usually straightforward once a doctor requests a genetic test known as karyotyping.
Sex chromosome number variations can be identified in pregnancy by counting chromosomes (karyotyping) in cell samples taken from placental tissue by CVS (chorionic villus sampling), or from fluid that surrounds the foetus (amniocentesis). Non-invasive prenatal testing using cells from maternal blood is often the first test undertaken known as the Harmony or NIPT test.
Many are diagnosed shortly after birth as a result of a chromosome tests run due to their small genitals. Other signs such as an unusual shaped head, unusually formed ears and broad forehead may also indicate a chromosomal disorder. Although a substantial proportion are diagnosed during their first year after development due to difficulty in taking longer to reach their developmental milestones.
Treatment
There is no cure for 49,XXXXY syndrome. Treatment depends on the features in each person and how severe the symptoms are. Early intervention is important as well as management by a multidisciplinary team to assist the individual.
An individual may need academic support as their ability to acquire academic skills will be affected. Also included in their specialist care might be a heart specialist (Cardiologist) as 15-20 percent of individuals with this disorder have a heart condition. Regular preventative treatment is needed as dental concerns are common. Additionally, orthopaedists, speech therapists, eye doctors (ophthalmologists) and neurologists can be helpful.
Most individuals with XXXXY will also need some occupational and physiotherapy in the early years to improve gross and fine motor skills. Individuals may also be prone to develop glue ear where the middle ear becomes filled with fluid and suffer ear infections and might need an ear specialist to assist with grommets.
An Endocrinologist also plays an important role in the care of the individual who can evaluate the individual to discuss treatment of testosterone replacement therapy due to lack of testosterone produced. This will also assist if the individual grows breast tissue and reduce this development. Testosterone therapy will also enlarge penis size and improve muscle bulk and protect against osteoporosis as well as help control adult height. Some families believe that it helps with behaviour management although others observe an increase in aggression.
With proactive management and effective treatment the impacts XXXXY has on a child and individuals life can be greatly decreased.
