XXYY syndrome

XXYY syndrome is a sex chromosome anomaly where males have two extra chromosomes: one X and one Y. Typically, human cells contain two sex chromosomes, one from each parent. Females usually have two X chromosomes (XX), while males have one X and one Y chromosome (XY). The presence of at least one Y chromosome with a functional SRY gene determines maleness. Thus, individuals with XXYY are genotypically male.

Males with XXYY syndrome possess 48 chromosomes instead of the usual 46, leading to the designation 48, XXYY syndrome or 48, XXYY. This condition affects approximately one in every 18,000–40,000 male births.

Signs and Symptoms

Common signs and symptoms of this condition include:

• Azoospermia

• Decreased testicular size

• Developmental delays

• Hypergonadotropic hypogonadism

• Sterility

• Intellectual impairment

• Speech impairment

Other frequent signs include:

• Abnormal dental enamel morphology

• Abnormal shoulder morphology

• Anxiety

• Asthma

• Attention-deficit hyperactivity disorder (ADHD) symptoms

• Autism spectrum disorders

• Blepharophimosis

• Caries

• Clinodactyly

• Constipation

• Delayed tooth eruption

• Depression

• Chronic otitis media

• Elbow dislocation

• Epicanthus

• Flat occiput

• Gynecomastia

• Hypertelorism

• Low muscle tone

• Joint hyperflexibility

• Obesity

• Open bite

• Flat feet

• Radioulnar synostosis

• Strabismus

• Tall stature

• Taurodontism

• Tremor

Additional symptoms may include:

• Learning disabilities

• Scoliosis

• Undescended testes

• Low testosterone

Cause

48,XXYY syndrome is associated with the X and Y chromosomes. Typically, individuals have 46 chromosomes in each cell. Two of these, the X and Y chromosomes, determine male or female sex characteristics. Females generally have two X chromosomes (46,XX), and males have one X and one Y chromosome (46,XY).

48,XXYY syndrome arises from an extra copy of both sex chromosomes in a male's cells (48,XXYY). Extra genes on the X chromosome disrupt male sexual development, impairing normal testicular function and reducing testosterone levels.

Many genes are exclusive to the X or Y chromosome, but those in the pseudoautosomal regions exist on both. Extra copies from these regions contribute to the syndrome's signs and symptoms, though specific genes remain unidentified.

Genetics

The 48,XXYY condition is not inherited; it typically occurs randomly during the formation of reproductive cells (eggs and sperm). An error in cell division, called nondisjunction, leads to a reproductive cell with an abnormal chromosome count. In 48,XXYY syndrome, the extra sex chromosomes usually originate from a sperm cell.

Nondisjunction can result in a sperm cell with two extra sex chromosomes, creating a sperm cell with three sex chromosomes (one X and two Y chromosomes). If this sperm fertilizes a normal egg with one X chromosome, the child will have two X and two Y chromosomes in each cell.

In a few cases, 48,XXYY syndrome results from nondisjunction of sex chromosomes in a 46,XY embryo shortly after fertilization. A normal sperm with one Y chromosome fertilizes a normal egg with one X chromosome, but post-fertilization nondisjunction adds two extra sex chromosomes, forming a 48,XXYY embryo.

Diagnosis

A karyotype is used to diagnose XXYY syndrome. Treatment involves medications, behavioral therapies, and extensive community support.

Management

Patients typically require monitoring by an endocrinologist. If hypogonadism is present, testosterone treatment should be considered for all, regardless of cognitive abilities, due to benefits for bone health, muscle strength, fatigue, and endurance, along with potential mental health improvements.

Most children with XXYY experience developmental delays and learning disabilities, necessitating evaluations in psychology, speech/language therapy, occupational therapy, and physical therapy. Consultation with a developmental pediatrician, psychiatrist, or neurologist is advised to develop a treatment plan including therapies, interventions, educational supports, and psychotropic medications for behavioral and psychiatric symptoms.

Common diagnoses like learning disability/ID, ADHD, autism spectrum disorders, mood disorders, tic disorders, and other mental health issues should be considered, screened for, and treated. Standard medications for inattention, impulsivity, anxiety, and mood instability often yield positive outcomes in this group, enhancing academic progress, emotional wellbeing, and long-term prospects.

Poor fine-motor coordination and intention tremor development can make handwriting challenging, so early introduction of occupational therapy and keyboarding is recommended to aid schoolwork and self-help skills. Educational difficulties require a full psychological evaluation to identify verbal and performance skill discrepancies and individual academic needs.

Expressive language skills often remain affected throughout life, necessitating speech therapy for expressive language skills, dyspraxia, and language pragmatics into adulthood. Weak adaptive skills (life skills) demand community-based support for nearly all adults. Additional treatment recommendations may be needed based on individual strengths and weaknesses in XXYY syndrome.

Prognosis

Patients generally have a normal life expectancy but require regular medical follow-ups.