XXY Syndrome

What It Is, Causes, Signs and Symptoms, Diagnosis, and More

Author: Emily Miao, MD, PharmD

Editor: Alyssa Haag, MD

Editor: Ian Mannarino MD, MBA

Editor: Kelsey LaFayette, DNP

Illustrator: Abbey Richard, MSc

Modified: Jan 06, 2025

What is XXY syndrome?

XXY syndrome, also known as Klinefelter syndrome (KS), is a genetic condition characterized by the presence of an extra X chromosome (47, XXY). Humans have 22 pairs of numbered chromosomes and one pair of sex chromosomes, resulting in a total of 46 chromosomes. Normally, those assigned males at birth have one X and one Y sex chromosome, but those with XXY syndrome, have an extra X chromosome resulting in physical, neurodevelopmental, and behavioral abnormalities. XXY syndrome is the most common sex chromosome disorder among humans and affects approximately 1 in 500 to 1,000 genetic males.

An infographic detailing the background, causes, signs and symptoms, diagnosis, and treatment of XXY syndrome.

What causes XXY syndrome?

XXY syndrome may be caused by a random error that occurs during meiosis (i.e., the process of producing gametes or sex cells) and therefore, is not inherited from parents. This results in all cells in the body having an extra copy of an X chromosome. In other cases, XXY syndrome may occur after the zygote (i.e., a product of a fertilized egg) becomes fertilized, during embryonic development. Mosaic Klinefelter syndrome can then occur, which is a variation of KS where some cells may have the normal XY genotype and other cells may have the XXY genotype, resembling a mosaic.

What are the signs and symptoms of XXY syndrome?

Signs and symptoms of XXY syndrome or Klinefelter syndrome vary between individuals. Most affected individuals are asymptomatic and do not display any symptoms of Klinefelter syndrome until they reach puberty or adolescence. During this period, children may not be able to progress through puberty. The most common symptoms include tall stature, reduced muscle tone, and lack of secondary sex characteristics such as facial and body hair. Affected genetic males may have structural genitourinary abnormalities, like hypospadias, which is an abnormal opening in the penis; testicular dysfunction resulting in small and firm gonads due to testicular fibrosis; weaker bones; infertility; and gynecomastia (i.e., enlargement of breast tissue in males). Developmental and behavioral abnormalities include poor muscle tone, speech-language delays, depression, ADHD, emotional immaturity, and mild impairments in executive functioning. Individuals with mosaic Klinefelter may display a milder spectrum of the aforementioned signs and symptoms compared to non-mosaic KS since some of their cells harbor the XY genotype. People with Klinefelter syndrome are at increased risk of endocrine dysfunction (e.g., diabetes mellitus, hypothyroidism), breast cancer, and autoimmune diseases.

How is XXY syndrome diagnosed?

Diagnosis of XXY syndrome begins with a thorough review of symptoms and medical history. Tanner staging is a system used to assess the stages of physical development during puberty and may reveal poorly developed or lack of secondary sex characteristics (e.g., lack of pubic hair, small testes) in affected individuals. Laboratory testing to evaluate hormone levels may reveal low testosterone levels and elevated luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Imaging studies such as pelvic ultrasound or magnetic resonance imaging (MRI) may be performed to assess the size and structure of the gonads. The diagnosis is confirmed via karyotyping or a chromosome analysis, which identifies the presence of an extra X chromosome. If there is suspicion of a chromosomal abnormality prenatally, amniocentesis (e.g., a procedure that involves removing a small sample of amniotic fluid) or chorionic villus sampling (i.e., a procedure that involves removing placental tissue) can be performed for further analysis.

How is XXY syndrome treated?

Men with Klinefelter syndrome are treated using a combination of pharmacologic and nonpharmacologic strategies to address symptoms and fertility problems and to improve their quality of life. Testosterone replacement therapy in the form of injections is administered monthly, starting at 4 to 12 months of age, to address the underlying testosterone deficiency. Testosterone replacement can improve energy levels and libido and facilitate the development of secondary sex characteristics. For fertility management, individuals may consider assisted reproductive technologies including in-vitro fertilization (i.e., the procedure whereby an egg is fertilized by sperm in a laboratory environment) with intracytoplasmic sperm injection using sperm that is donated or retrieved from the individual. Early interventions such as speech, language, and special education services may help address speech impairments and developmental delays. A primary care provider can help prevent and manage associated health problems such as osteoporosis, diabetes, and heart disease.

What are the most important facts to know about XXY syndrome?

XXY syndrome also known as Klinefelter syndrome, is a genetic condition characterized by the presence of an extra X chromosome (47, XXY). Klinefelter syndrome occurs in approximately 1 in 500 to 1,000 males in the United States. In some cases, XXY syndrome may occur after the zygote becomes fertilized, during embryonic development, which results in a variation of KS called mosaic Klinefelter, where some cells may have the normal XY genotype. Men with Klinefelter syndrome are typically taller than average and display signs and symptoms that reflect testosterone deficiency, which include low energy, libido, reduced muscle mass, and lack of secondary sex characteristics. Diagnosis is confirmed with genetic testing through karyotyping, which reveals an extra X chromosome. Treatment consists of hormone replacement therapy, reproductive assistive technologies, and supportive interventions to improve the individual’s quality of life.

References

Akcan N, Poyrazoğlu Ş, Baş F, Bundak R, Darendeliler F. Klinefelter syndrome in childhood: Variability in clinical and molecular findings. J Clin Res Pediatr Endocrinol. 2018;10(2):100-107. doi:10.4274/jcrpe.5121

Bojesen A, Juul S, Gravholt CH. Prenatal and postnatal prevalence of Klinefelter syndrome: A national registry study. J Clin Endocrinol Metab. 2003;88(2):622-626. doi:10.1210/jc.2002-021491

Bonomi M, Rochira V, Pasquali D, et al. Klinefelter syndrome (KS): Genetics, clinical phenotype and hypogonadism. J Endocrinol Invest. 2017;40(2):123-134. doi:10.1007/s40618-016-0541-6

Davis S, Howell S, Wilson R, et al. Advances in the interdisciplinary care of children with klinefelter syndrome. Adv Pediatr. 2016;63(1):15-46. doi:10.1016/j.yapd.2016.04.020

Groth KA, Skakkebæk A, Høst C, Gravholt CH, Bojesen A. Clinical review: Klinefelter syndrome--A clinical update. J Clin Endocrinol Metab. 2013;98(1):20-30. doi:10.1210/jc.2012-2382

Lanfranco F, Kamischke A, Zitzmann M, Nieschlag E. Klinefelter's syndrome. Lancet. 2004;364(9430):273-283. doi:10.1016/S0140-6736(04)16678-6

Ross JL, Kushner H, Kowal K, et al. Androgen treatment effects on motor function, cognition, and behavior in boys with Klinefelter syndrome. J Pediatr. 2017;185:193-199.e4. doi:10.1016/j.jpeds.2017.02.036