XXYY syndrome

XXYY syndrome
Other names	48,XXY Y Klinefelter syndrome (archaic); 48,XXYY variant of Klinefelter's syndrome (archaic)
XXYY syndrome

XXYY syndromeis asex chromosomeanomaly in which males have 2 extrachromosomes,oneXand oneY chromosome.Human cellsusually contain two sex chromosomes, one from the mother and one from the father. Usually, females have two X chromosomes (XX) and males have one X and one Y chromosome (XY). The appearance of at least one Y chromosome with a properly functioningSRYgenemakes a male. Therefore, humans with XXYY aregenotypicallymale. Males with XXYY syndrome have 48 chromosomes instead of the typical 46. This is why XXYY syndrome is sometimes written as48, XXYY syndromeor48, XXYY.It affects an estimated one in every 18,000–40,000 male births.

Presentation

Very frequent signs and symptoms of this condition include the following:

• Azoospermia
• Decreased testicular size
• Developmental delays
• Hypergonadotropic hypogonadism
• Sterility
• Intellectual impairment
• Speech impairment

Other frequent signs of this condition include the following:

• Abnormaldental enamelmorphology
• Abnormal shoulder morphology
• Anxiety
• Asthma
• Attention-deficit hyperactivity disorder(ADHD) symptoms
• Autism spectrumdisorders
• Blepharophimosis
• Caries
• Clinodactyly
• Constipation
• Delayedtooth eruption
• Depression
• Chronicotitis media
• Elbow dislocation
• Epicanthus
• Flatocciput
• Gynecomastia
• Hypertelorism
• Lowmuscle tone
• Joint hyperflexibility
• Obesity
• Open bite
• Flat feet
• Radioulnar synostosis
• Strabismus
• Tall stature
• Taurodontism

• Tremor

Other symptoms may include the following:

• Learning disabilities
• Scoliosis
• Undescended testes
• Lowtestosterone

Cause

48,XXYY syndrome is a condition related to the X and Y chromosomes (the sex chromosomes). People normally have 46 chromosomes in eachcell.Two of the 46 chromosomes, known as X and Y, are called sex chromosomes because they help determine whether a person will develop male or femalesex characteristics.Females typically have two X chromosomes (46,XX), and males have one X chromosome and one Y chromosome (46,XY). 48,XXYY syndrome results from the presence of an extra copy of both sex chromosomes in each of a male's cells (48,XXYY). Extra copies of genes on the X chromosome interfere with male sexual development, preventing thetestesfrom functioning normally and reducing the levels oftestosterone.Many genes are found only on the X or Y chromosome, but genes in areas known as thepseudoautosomal regionsare present on both sex chromosomes. Extra copies of genes from the pseudoautosomal regions of the extra X and Y chromosome contribute to the signs and symptoms of 48,XXYY syndrome; however, the specific genes have not yet been identified.

Genetics

The condition 48,XXYY is notinherited;it usually occurs as a random event during the formation ofreproductive cells(eggs and sperm). An error in cell division callednondisjunctionresults in a reproductive cell with an abnormal number of chromosomes. In 48,XXYY syndrome, the extra sex chromosomes almost always comes from asperm cell.Nondisjunction may cause a sperm cell to gain two extra sex chromosomes, resulting in a sperm cell with three sex chromosomes (one X and two Y chromosomes). If that sperm cell fertilizes a normal egg cell with one X chromosome, the resulting child will have two X chromosomes and two Y chromosomes in each of his body's cells.

In a small percentage of cases, 48,XXYY syndrome results from nondisjunction of the sex chromosomes in a 46,XYembryovery soon afterfertilizationhas occurred. This means that a normal sperm cell with one Y chromosome fertilized a normal egg cell with one X chromosome, but right after fertilization, nondisjunction of the sex chromosomes caused the embryo to gain two extra sex chromosomes, resulting in a 48,XXYY embryo.

Diagnosis

Akaryotypeis done to diagnose XXYY syndrome. Treatment consists of medications, behavioral therapies, and intensive community support.

Management

Patients generally need to be followed by anendocrinologist.Ifhypogonadismis present, testosterone treatment should be considered in all individuals regardless ofcognitiveabilities due to positive effects on bone health, muscle strength, fatigue, and endurance, with possible mental health/behavioral benefits, as well.

Most children with XXYY have some developmental delays and learning disabilities. Therefore, these aspects should be checked and monitored: psychology (cognitive and social–emotional development), speech/language therapy, occupational therapy, and physical therapy. Consultation with a developmental pediatrician,psychiatrist,orneurologistto develop a treatment plan including therapies, behavioral interventions, educational supports, andpsychotropic medicationsfor behavioral and psychiatric symptoms should be arranged.

Common diagnoses such as learning disability/ID, ADHD, autism spectrum disorders, mood disorders, tic disorders, and other mental health problems should be considered, screened for, and treated. Good responses to standard medication treatments forinattention,impulsivity,anxiety,and mood instability are seen in this group, and such treatment can positively impact academic progress, emotional wellbeing, and long-term outcome. Poorfine-motor coordinationand the development ofintention tremorcan make handwriting slow and laborious, and occupational therapy andkeyboardingshould be introduced at an early age to facilitate schoolwork and self-help skills. Educational difficulties should be evaluated with a full psychological evaluation to identify discrepancies between verbal and performance skills and to identify individual academic needs.

Expressive language skills are often affected throughout life, and speech therapy interventions targeting expressive language skills,dyspraxia,and language pragmatics may be needed into adulthood. Adaptive skills (life skills) are a significant area of weakness, necessitating community-based supports for almost all individuals in adulthood.Additional treatment recommendations based on the individual strengths and weaknesses in XXYY syndrome may be required.

Prognosis

Patients have an essentially normal life expectancy, but require regular medical follow-ups.

History

The first published report of a boy with a 48,XXYY karyotype was by Sylfest Muldal and Charles H. Ockey inManchester,Englandin 1960. It was described in a 15-year-old mentally disabled boy who showed signs ofKlinefelter syndrome;however, chromosome testing revealed 48,XXYY instead of the 47, XXY arrangement known to cause Klinefelter syndrome. Because of this, 48,XXYY syndrome was originally considered a variation of Klinefelter syndrome. Shared physical and medical features resulting from the presence of an extra X chromosome include tall stature, the development oftestosterone deficiencyin adolescence and/or adulthood (hypergonadotropic hypogonadism), andinfertility.However, recent research shows some important differences in males with 48,XXYY compared to 47, XXY.The most important differences result from the effects of the extra X and Y chromosome on neurodevelopment, leading to higher rates of developmental delays in early childhood, learning disability or intellectual disability, adaptive functioning (life skills) difficulties,neurodevelopmental disorderssuch asADHDorautism spectrumdisorders, and psychological/behavioral problems includinganxiety,depression,andmood dysregulation.Also, a larger percentage of males with XXYY have additional medical problems such asseizures,congenital elbow malformations (radioulnar synostosis), and tremor compared to males with XXY. XXYY is still considered a variation of Klinefelter syndrome by some definitions, mainly because thepathophysiologyof the testicular dysfunction has not been shown to differ from 47, XXY, and the most current research does not suggest that there should be any differences in the evaluation and treatment of testosterone deficiency in 48,XXYY compared to 47, XXY.However, for the psychological and behavioral symptoms of XXYY syndrome, more extensive evaluations, interventions, and supports are usually needed compared to 47, XXY due to more complexneurodevelopmentalinvolvement. Significant variability is seen between individuals in the number and severity of the medical and neurodevelopmental problems associated with XXYY, and some individuals have mild symptoms, while others are more significantly affected.

See also

• Aneuploidy
• Tetrasomy X
• Taurodontism