XXXXY syndrome

XXXXY syndrome, also referred to as 49,XXXXY syndrome or Fraccaro syndrome, is a very rare aneuploidic sex chromosomal disorder. It affects approximately 1 in 85,000 to 100,000 males. This condition is caused by maternal non-disjunction during both meiosis I and II. First identified in 1960, it was named Fraccaro syndrome after the researcher who discovered it.

Signs and symptoms

The symptoms of 49,XXXXY bear some resemblance to those of Klinefelter syndrome and 48,XXXY, but they are generally more severe. Aneuploidy is often lethal, but due to "X-inactivation", the impact of the extra gene dosage from additional X chromosomes is significantly reduced.

Reproductive

Individuals with 49,XXXXY syndrome typically show underdeveloped secondary sex characteristics and experience sterility in adulthood.

• Hypoplastic genitalia

• Absent or delayed puberty

Physical

Males with 49,XXXXY often have multiple skeletal anomalies, including:

• Genu valgum

• Pes cavus

• Fifth finger clinodactyly

Other effects include:

• Cleft palate

• Club feet

• Respiratory conditions

• Short and/or 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 linked to higher rates of primary immunodeficiency.

Cognitive and developmental

Similar to Down syndrome, the cognitive effects of 49,XXXXY syndrome vary. Impaired speech and maladaptive behavioral issues are common. A study examined males diagnosed with 48,XXYY, 48,XXXY, and 49,XXXXY, finding that males with 48,XXXY and 49,XXXXY operate at a much lower cognitive level than their peers. These individuals also tend to display behavior that is less mature for their age, with increased aggressive tendencies noted in the study.

A 2020 study revealed that boys with 49,XXXXY exhibit higher rates of internalizing behavior and anxiety, starting as early as preschool. Tests using the Social Responsiveness Scale-2 (SRS-2) indicated that while individuals with the condition generally showed more signs of social impairment, their social awareness was minimally affected.

Pathophysiology

As the name suggests, a person with this syndrome has one Y chromosome and four X chromosomes on the 23rd pair, resulting in forty-nine chromosomes instead of the usual forty-six. Like most aneuploidy disorders, 49,XXXXY syndrome is often associated with intellectual disability. It can be considered a 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 although the parents' genes cause the syndrome, the likelihood of having more than one child with the syndrome is low. The chance of inheriting the disorder is about one percent.

Diagnosis

49,XXXXY can be clinically diagnosed through karyotyping. Facial dysmorphia and other somatic abnormalities may prompt genetic testing.

Treatment

While there is no treatment to correct the genetic anomaly of this syndrome, its symptoms can be managed. Due to infertility, one man from Iran used artificial reproductive techniques. An infant in Iran diagnosed with 49,XXXXY syndrome was born with patent ductus arteriosus, which was corrected surgically, and other complications that were addressed with replacement therapy.

Testosterone therapy has been shown to enhance motor skills, speech, and nonverbal IQ in males with 49,XXXXY.