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(XXY Syndrome)

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About 1 in every 500 to 800 males is born with this disorder. 3000 boys every year. 3% of infertile male population have Klinefelter Syndrome

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There are many support groups for men with Klinefelter Syndrome. There are organizations that help men and women find support groups such as NORD.

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NORD (National Organization for Rare Disorders)

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NORD gratefully acknowledges Dr. Carole Samango-Sprouse, Associate Clinical Professor in the Department of Pediatrics at George Washington University and Adjunct Associate Professor in the Department of Human and Molecular Genetics at Florida International University, for assistance in the preparation of this report.

Synonyms of 47,XXY (Klinefelter Syndrome)

General Discussion
Summary
Klinefelter Syndrome (47, XXY) is a chromosomal variation in males in which one extra X chromosome is present, resulting in a 47,XXY karyotype. The extra X chromosome typically affects physical, neurodevelopmental, behavioral, and neurocognitive functioning. Common physical features may include tall stature, reduced muscle tone, small testes (hypogonadism), delayed pubertal development and lack of secondary male sex characteristics such as decreased facial and body hair. Increased breast growth (gynecomastia) may occur later in puberty without appropriate biological care. With proper treatment, the incidence of gynecomastia typically occurs in less than 10% of boys with 47,XXY (KS).

There is great variability to the neurodevelopmental profile or phenotype in boys with 47,XXY (KS). Common cognitive and behavioral features may include speech and language delays, ADHD and emotional and social functioning challenges. The features of 47, XXY (KS) are typically associated with decreased testosterone level and elevated gonadotropin levels. Early hormonal treatment (EHT) with three monthly injections of 25 mg. of testosterone enanthate, typically given between 4-12 months of age, may optimize brain development and neurodevelopmental outcomes. Testosterone should be administered based upon an evaluation with a pediatrician and pediatric endocrinologist familiar with 47,XXY (KS).

Signs & Symptoms

At birth, most neonates with 47, XXY (KS) have no significant dysmorphic or unusual features. Most individuals with 47, XXY (KS) are identified though prenatal diagnosis or when the child does not progress through puberty completely or adequately. Infants and young children with 47, XXY (KS) are sometimes initially identified because of an abnormality in the location of the urinary opening in the penis (hypospadias), small penis or testes, or developmental delay (e.g. speech delay). Older children and teenagers are sometimes diagnosed with 47, XXY (KS) if secondary sexual characteristics do not develop completely, puberty is delayed, testes are small, or breast development occurs. Many males with 47, XXY (KS) are not identified until they have low fertility problems as adults. Men with 47, XXY (KS) may have a relatively increased risk to develop breast cancer but not until after 60 years of age. Most males with 47, XXY (KS) have normal intelligence but there is an increased risk of language based learning disorders, dyslexia and mild social and executive functioning challenges. Often, boys and men with 47, XXY (KS) will present with verbal communication delays due to language-based learning disorders and subtle motor planning deficits. Research has shown, however, that nonverbal capacities in males with 47, XXY (KS), such as perceptual reasoning and receptive language skills, may be intact or even advanced. Thus, PIQ (nonverbal IQ) is often higher than VIQ (verbal IQ) on neurodevelopmental testing. Socially, males with 47, XXY (KS) may have difficulty perceiving social cues and regulating their emotions in stressful situations.

Men with 47, XXY (KS) may have an increased risk for endocrine conditions such as diabetes mellitus, hypothyroidism and hypoparathyroidism and autoimmune diseases such as systemic lupus erythematosus, Sjogren syndrome and rheumatoid arthritis. Many of these conditions can be treated with medications and lifestyle changes.

Causes

47, XXY (KS) is not inherited. Males with 47, XXY (KS) have one extra X chromosome because of a nondisjunction error that randomly occurs during the division of the sex chromosomes in the egg or sperm. Some males with 47, XXY (KS) are mosaic, meaning that some cells have an extra X chromosome and other cells do not. Mosaic 47, XXY (KS) occurs because of an error in the division of the sex chromosomes in the zygote after fertilization. The extra X chromosome typically results in primary testicular failure leading to androgen deficiency.

Affected Populations

47, XXY (KS) is the most common human sex chromosome disorder and occurs in approximately 1 in 500-1,000 males. It is estimated that 3,000 affected boys are born each year in the United States.

Diagnosis

Males with 47, XXY (KS) are most commonly identified before birth (e.g. through prenatal screenings for chromosomal disorders), at puberty or later in life because of low fertility. 47, XXY (KS) is diagnosed by a chromosome karyotype analysis on a blood sample or by a chromosomal microarray (CMA) test. CMA consists of an oral cheek (buccal) swab and is an easy and painless way to detect abnormalities of chromosome numbers and provide a definitive diagnosis. 47, XXY (KS) can also be diagnosed prenatally on chorionic villous or amniotic fluid cells.

Standard Therapies

Treatment
One of the hallmarks of Klinefelter syndrome is hypergonadotropic hypogonadism, a condition that results in testosterone deficiency. Treatment involves the targeted administration of male hormones (androgens), such as testosterone enanthate, cypionate, or androgel. Early hormonal treatment (EHT), three monthly injections of 25 mg of testosterone enanthate, is typically administered between 4-12 months of age. These hormones are given to promote the development of secondary male sexual characteristics (virilization) and alleviate feminization effects that have occurred due to insufficient testosterone levels. Hormone replacement therapy is effective when initiated during early infancy or around pubertal development or even later in life. Some men with 47, XXY (KS) who have gynecomastia may elect to have surgical breast reduction for cosmetic purposes. This procedure often may be avoided if proper and timely dosage of testosterone as well as estrogen inhibitor is administered to an individual, although it varies with each individual.

As infants, these boys need to be monitored for positional torticollis which can be treated with pediatric physical therapy. Speech and language therapy, physical therapy and occupational therapy are often helpful for boys with 47, XXY (KS). These interventions are shown to significantly improve academic, physical, cognitive, and social outcomes in boys with 47, XXY (KS). A comprehensive psychoeducational evaluation is recommended to determine what resources may be helpful in the classroom. Social skills training classes can also be beneficial.

Men with 47, XXY (KS) have low fertility, and with novel assistive and reproductive techniques, more men with 47, XXY (KS) have the opportunity to reproduce a child. Men with mosaic 47, XXY (KS) have higher likelihood of fewer complications with reproduction. Surgical extraction of sperm from the testes and intracytoplasmic sperm injection (ICSI) directly into an ovum is a medical technology available to assist men with 47, XXY (KS) father children.

Investigational Therapies

NORD Member Organizations

Other Organizations

References

TEXTBOOK
Samango-Sprouse, C, and Gropman, AL. X & Y chromosomal variations: hormones, brain development, and neurodevelopmental performance. San Rafael, CA: Morgan & Claypool Publishers, 2017.

Visootsak, J, Graham, JM, Samango-Sprouse, C, Swerdloff, R, Simpson, JL. Management of Genetic Syndromes 3rd Edition: Klinefelter Syndrome. Cassidy, SB, and Allanson, JE eds. WileyLiss, 2008.

JOURNAL ARTICLES
Samango-Sprouse, CA, Counts DR, Tran SL, Lasutschinkow PC, Porter GF, Gropman AL. Update on the clinical perspectives and care of the child with 47,XXY (Klinefelter syndrome). Appl Clin Genet. 2019;12:191-202. Published 2019 Oct 23. Doi:10.2147/TACG.S180450

Samango-Sprouse, C; Hall, MP; Kırkızlar, E; Curnow, K; Demko, Z; Lawson, P; Gross,S; Gropman, A. Incidence of X and Y chromosomal aneuploidy in a large child bearing population. Public Library of Science. Plos ONE. 2016; April 11(8), 1-11. doi:10.1371/journal.pone.0161045.

Samango‐Sprouse C, Stapleton EJ, Lawson P, Mitchell F, Sadeghin T, Powell S, Gropman AL. Positive effects of early androgen therapy on the behavioral phenotype of boys with 47, XXY. American Journal of Medical Genetics Part C: Seminars in Medical Genetics 2015 Jun 1 (Vol. 169, No. 2, pp. 150-157.

Wosnitzer, M S and Paduch, D A., Endocrinological issues and hormonal manipulation in children and men with Klinefelter syndrome. Am. J. Med. Genet. 2013;163: 16-26.

Samango-Sprouse CA, Gropman AL, Sadeghin T, et al. Effects of short-course androgen therapy on the neurodevelopmental profile of infants and children with 49,XXXXY syndrome. Acta Paediatr. 2011;100(6):861-5.

Tartaglia N, Ayari N, Howell S, D'Epagnier C, Zeitler P. 48, XXYY, 48, XXXY and 49, XXXXY syndromes: not just variants of Klinefelter syndrome. Acta paediatrica. 2011 Jun 1;100(6):851-60.

Samango-Sprouse CA. Expansion of the phenotypic profile of the young child with XXY. Pediatr Endocrinol Rev. 2010;8 Suppl 1:160-8.

van Rijn S, Swaab H, Aleman A, Kahn RS. X Chromosomal effects on social cognitive processing and emotion regulation: A study with Klinefelter men (47, XXY). Schizophrenia Res. 2008; 84(2):194-203.

Visootsak J, Graham JM Jr. Klinefelter syndrome and other sex chromosomal aneuploidies. Orphanet J Rare Dis. 2006;1:42.

Wikstrom AM, Painter JN, Raivio T, Aittomaki K, Dunkel L. Genetic features of the X chromosome affect pubertal development and testicular degeneration in adolescent boys with Klinefelter syndrome. Clin Endocrinol (Oxf). 2006;65(1):92-7.

Schiff JD, Palermo GD, Veeck LL, et al. Success of testicular sperm injection and intracytoplasmic sperm injection in men with Klinefelter syndrome. J Clin Endocrinol Metab. 2005;90(11):6263-7.

Swerdlow AJ, Higgins CD, Schoemaker MJ, et al. Mortality in patients with Klinefelter syndrome in Britain: a cohort study. J Clin Endocrinol Metab. 2005;90(12):6516-22.

Swerdlow AJ, Schoemaker MJ, Higgins CD, Wright AF, Jacobs PA. Cancer incidence and mortality in men with Klinefelter syndrome: a cohort study. J Natl Cancer Inst. 2005;97(16):1204-10.

Wattendorf DJ, Muenke M. Klinefelter syndrome. Am Fam Physician. 2005;72(11):2259- 62.

Denschlag D, Tempfer C, Kunze M, Wolff G, Keck C. Assisted reproductive techniques in patients with Klinefelter syndrome: a critical review. Fertil Steril. 2004;82(4):775-9.

Bojesen A, Juul S, Gravholt CH. Prenatal and postnatal prevalence of Klinefelter syndrome: a national registry study. J Clin Endocrinol Metab. 2003;88(2):622-6.

Kamischke A, Baumgardt A, Horst J, Nieschlag E. Clinical and diagnostic features of patients with suspected klinefelter syndrome. J Androl. 2003;24(1):41-8.

Hultborn R, Hanson C, Köpf I, Verbiené I, Warnhammar E, & Weimarck A. Prevalence of Klinefelter's syndrome in male breast cancer patients. Anticancer Res. 1997; 17(6D), 4293-4297.

Linden MG, Bender BG, Robinson A. Sex chromosome tetrasomy and pentasomy. Pediatrics. 1995;96(4 Pt 1):672-82.

Kleczkowska A, Fryns JP, Van den Berghe H. X-chromosome polysomy in the male. The Leuven experience 1966-1987. Hum Genet.1988;80(1):16-22.

Bender BG, Puck MH, Salbenblatt JA, Robinson A. Dyslexia in 47, XXXY boys identified at birth. Behavior genetics. 1986 May 1;16(3):343-54.

Evans JA, de von Flindt R, Greenberg C, Ramsay S, Hamerton JL. A cytogenetic survey of 14,069 newborn infants. IV. Further follow-up on the children with sex chromosome anomalies. Birth defects original article series. 1981 Dec;18(4):169-84.

Years Published

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47,XXY (Klinefelter Syndrome) - NORD (National Organization for Rare Disorders)

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NORD gratefully acknowledges Dr. Carole Samango-Sprouse, Associate Clinical Professor in the Department of Pediatrics at George Washington University and Adjunct Associate Professor in the Department of Human and Molecular Genetics at Florida International University, for assistance in the preparation of this report.

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Current status of research for Klinefelter Syndrome

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Current status of research for Klinefelter Syndrome

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Research is currently being done to find ways to hopefully prevent and one day cure Klinefelter Syndrome.

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Klinefelter Syndrome (KS): Research Activities and Scientific Advances

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Institute Activities and Advances Other Activities and Advances Institute Activities and Advances KS can influence many aspects of a person's entire life, starting very soon after conception. Therefore, many branches, sections, and laboratories at NICHD conduct research that is relevant to males with XXY or poly-KS variations.

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Long-Term Outlook for an Individual with this Disorder

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Long-Term Outlook for an Individual with this Disorder

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Babies may struggle with speech and walking. Boys may struggle with adolescence with difficulties growing up. Some have ended up to have no issues and live an average, successful life. Lifespan is not affected by this condition.

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The following information may help to address your question:

What is Klinefelter syndrome?

Klinefelter syndrome (KS) is a condition that occurs in males when they have an extra X chromosome. Some males with KS have no obvious signs or symptoms while others may have varying degrees of cognitive, social, behavioral, and learning difficulties. Adults with Klinefelter syndrome may also have primary hypogonadism (decreased testosterone production), small and/or undescendent testes (cryptorchidism), enlarged breast tissue ( gynecomastia), tall stature, and/or inability to have biological children (infertility), as well as an abnormal opening of the penis (hypospadias), and an small penis (micropenis). KS is not inherited, but usually occurs as a random event during the formation of reproductive cells (eggs and sperm) that results in the presence of one extra copy of the X chromosome in each cell (47,XXY). KS treatment is based on the signs and symptoms present in each person. Life expectancy is usually normal and many people with KS have normal life. There is a very small risk of developing breast cancer and other conditions such as a chronic inflammatory disease called systemic lupus erythematosus.

In some cases, there is more than one X chromosome in each cell (for example, 48,XXXY or 49,XXXXY). These conditions, which are often called "variants of Klinefelter" syndrome usually have more serious problems ( intellectual disability, skeletal problems, and poor coordination) than classic Klinefelter syndrome (47,XXY).

What are the signs and symptoms of Klinefelter syndrome?

The signs and symptoms of Klinefelter syndrome (KS) vary among affected people. Some men with KS have no symptoms of the condition or are only mildy affected. In these cases, they may not even know that they are affected by KS. When present, symptoms may include:

Small, firm testicles

Delayed or incomplete puberty with lack of secondary sexual characteristics resulting in sparse facial, body, or sexual hair a high-pitched voice and body fat distribution resulting in a rounder, lower half of the body, with more fat deposited in the hips, buttocks and thigh instead of around the chest and abdomen

Breast growth (gynecomastia)

Reduced facial and body hair

Infertility

Tall stature

Abnormal body proportions (long legs, short trunk, shoulder equal to hip size)

Learning disablity

Speech delay

Crypthochirdism

Opening (meatus) of the urethra (the tube that carries urine and sperm through the penis to the outside) on the underside of the penis (hypospadias) instead of the tip of the head of the penis

Social, psychologic and behavioral problems

Whether or not a male with KS has visible symptoms depends on many factors, including how much testosterone his body makes, if he is mosaic (with both XY and XXY cells), and his age when the condition is diagnosed and treated. Some people have a slightly increased risk of developing breast cancer, a rare extragonadal germ cell tumor, lung disease, varicose veins and osteoporosis as well as some autoimmune disorders such as systemic lupus erythematosus, rheumatoid arthritis and Sjogren's syndrome.
Some people with features of Klinefelter syndrome have more than one extra X chromosome in each cell (such as 48,XXXY or 49,XXXXY). In these cases, known as "variants of Klinefelter syndrome", the signs and symptoms can be more severe and may include:

Intellectual disability

Distinctive facial features

Skeletal abnormalities

Poor coordination

Severe speech difficulties

Behavioral problems

Heart defects

Teeth problems.

What causes Klinefelter syndrome?

Klinefelter syndrome usually occurs as a random event during the formation of reproductive cells (eggs and sperm). An error in cell division called nondisjunction results in a reproductive cell with an abnormal number of chromosomes. For example, an egg or sperm cell may gain one or more extra copies of the X chromosome as a result of nondisjunction. If one of these atypical reproductive cells contributes to the genetic makeup of a child, the child will have one or more extra X chromosomes in each of the body's cells.

Most often, Klinefelter syndrome is caused by a single extra copy of the X chromosome, resulting in a total of 47 chromosomes per cell. Males normally have one X chromosome and one Y chromosome in each cell (46, XY), while females have two X chromosomes (46, XX). People with Klinefelter syndrome usually have two X chromosomes and one Y chromosome (47, XXY). Some people with Klinefelter syndrome have the extra X chromosome in only some of their cells; these people are said to have mosaic Klinefelter syndrome.

It is estimated that about half of the time, the cell division error occurs during development of the sperm, while the remainder are due to errors in egg development. Women who have pregnancies after age 35 have a slightly increased chance of having offspring with this syndrome.

The features of Klinefelter syndrome are due to the extra copies of genes on the extra X chromosome, which can alter male sexual development.

Some people with features of Klinefelter syndrome have conditions known as "variants of Klinefelter syndrome" where there is more than one extra sex chromosome in each cell ( 48,XXXY, 48,XXYY and 49,XXXXY).

How might Klinefelter syndrome be treated?

Because symptoms of Klinefelter syndrome (KS) can sometimes be very mild, many people are never diagnosed or treated. When a diagnosis is made, treatment is based on the signs and symptoms present in each person, especially the problems related to hypogonadism, gynecomastia, and psychosocial problems. Treatment may include:

Testosterone replacement: About half of people with SK have low testosterone levels, which may be raised by taking supplemental testosterone. Having a more normal testosterone level can help affected people develop bigger muscles, a deeper voice, and facial and body hair, and may also increase sexual desire, enlarge the testes, improve mood, self-image, and behavior; it may also protect against osteoporosis and decrease the risks of autoimmune disease and breast cancer.

Breast removal or reduction surgery.

Educational interventions: As children, many people with Klinefelter syndrome qualify for special services to help them in school. Teachers can also help by using certain methods in the classroom, such as breaking bigger tasks into small steps.

Several forms of therapy such as physical, speech, occupational, behavioral, mental health, and family therapy can often help reduce or eliminate some of the symptoms of Klinefelter syndrome such as poor muscle tone; speech and language problems; or low self-confidence.

What is the long-term outlook for people with Klinefelter syndrome?

Babies with the 47, XXY form of Klinefelter differ little from healthy children. The results of one study on non- mosaic XXY infants younger than 2 years indicated that most XXY babies had normal external genitalia and facial features with height and weight in the normal range. Genetic testing had been performed due to a delay in walking and/or speech. Early diagnosis of Klinefelter syndrome is shown to be important to monitor potential developmental problems.

Boys with the 47, XXY karyotype may struggle through adolescence with academics, various frustrations, and, in a few instances, serious emotional or behavioral difficulties. However, most move toward full independence from their families as they enter adulthood. Some have completed graduate education and have a normal level of functioning. Lifespan is not affected by Klinefelter syndrome.

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We hope this information is helpful. We strongly recommend you discuss this information with your doctor. If you still have questions, please contact us.

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GARD Information Specialist

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The following information may help to address your question: What is Klinefelter syndrome? Klinefelter syndrome (KS) is a condition that occurs in males when they have an extra X chromosome. Some males with KS have no obvious signs or symptoms while others may have varying degrees of cognitive, social, behavioral, and learning difficulties.

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There are currently no cures or ways to remove the extra X chromosome. Although there are ways to treat the symptoms affected by the person.

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Is there a cure for Klinefelter syndrome (KS)?

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Currently, there is no way to remove chromosomes from cells to "cure" the XXY condition. But many symptoms can be successfully treated, minimizing the impact the condition has on length and quality of life.

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Who Is Most Likely to be affected by Klinefelter Syndrome

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Who Is Most Likely to be affected by Klinefelter Syndrome

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Klinefelter Syndrome can affect any male. It is usually diagnosed in adulthood.

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Symptoms and effects on the individual with this disorder

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Symptoms and effects on the individual with this disorder

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Some males may have low testerone and reduced muscle mass, facial and body hair. They can be taller, have longer legs and broader hips compared to most average males. Puberty may be delayed and their development may be overall weak and not average. It also affects them when learning because they tend to be more slow with their energy levels, information processing skills, and difficulty expressing themselves.

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Yes, there are prenatal tests. The doctor would do hormone tests or a sperm analysis.

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Some of the body cells have the regular chromosome (XY) while others have an extra X chromosome (XXY) included.

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Description

Klinefelter syndrome is a chromosomal condition in boys and men that can affect physical and intellectual development. Most commonly, affected individuals are taller than average are unable to father biological children (infertile); however the signs and symptoms of Klinefelter syndrome vary among boys and men with this condition. In some cases, the features of the condition are so mild that the condition is not diagnosed until puberty or adulthood, and researchers believe that up to 75 percent of affected men and boys are never diagnosed.

Boys and men with Klinefelter syndrome typically have small testes that produce a reduced amount of testosterone (primary testicular insufficiency). Testosterone is the hormone that directs male sexual development before birth and during puberty. Without treatment, the shortage of testosterone can lead to delayed or incomplete puberty, breast enlargement (gynecomastia), decreased muscle mass, decreased bone density, and a reduced amount of facial and body hair. As a result of the small testes and decreased hormone production, affected males are infertile but may benefit from assisted reproductive technologies. Some affected individuals also have differences in their genitalia, including undescended testes (cryptorchidism), the opening of the urethra on the underside of the penis (hypospadias), or an unusually small penis (micropenis).

Other physical changes associated with Klinefelter syndrome are usually subtle. Older children and adults with the condition tend to be somewhat taller than their peers. Other differences can include abnormal fusion of certain bones in the forearm (radioulnar synostosis), curved pinky fingers (fifth finger clinodactyly), and flat feet ( pes planus).

Children with Klinefelter syndrome may have low muscle tone (hypotonia) and problems with coordination that may delay the development of motor skills, such as sitting, standing, and walking. Affected boys often have learning disabilities, resulting in mild delays in speech and language development and problems with reading. Boys and men with Klinefelter syndrome tend to have better receptive language skills (the ability to understand speech) than expressive language skills (vocabulary and the production of speech) and may have difficulty communicating and expressing themselves.

Individuals with Klinefelter syndrome tend to have anxiety, depression, impaired social skills, behavioral problems such as emotional immaturity and impulsivity, attention-deficit/hyperactivity disorder (ADHD), and limited problem-solving skills (executive functioning). About 10 percent of boys and men with Klinefelter syndrome have autism spectrum disorder.

Nearly half of all men with Klinefelter syndrome develop metabolic syndrome, which is a group of conditions that include type 2 diabetes, high blood pressure ( hypertension), increased belly fat, high levels of fats (lipids) such as cholesterol and triglycerides in the blood. Compared with unaffected men, adults with Klinefelter syndrome also have an increased risk of developing involuntary trembling (tremors), breast cancer (if gynecomastia develops), thinning and weakening of the bones (osteoporosis), and autoimmune disorders such as systemic lupus erythematosus and rheumatoid arthritis. (Autoimmune disorders are a large group of conditions that occur when the immune system attacks the body's own tissues and organs.)

Frequency

Klinefelter syndrome affects about 1 in 650 newborn boys. It is among the most common sex chromosome disorders, which are conditions caused by changes in the number of sex chromosomes (the X chromosome and the Y chromosome).

Causes

Klinefelter syndrome is a sex chromosome disorder in boys and men that results from the presence of an extra X chromosome in cells. People typically have 46 chromosomes in each cell, two of which are the sex chromosomes. Females have two X chromosomes (46,XX), and males have one X and one Y chromosome (46,XY). Most often, boys and men with Klinefelter syndrome have the usual X and Y chromosomes, plus one extra X chromosome, for a total of 47 chromosomes (47,XXY).

Boys and men with Klinefelter syndrome have an extra copy of multiple genes on the X chromosome. The activity of these extra genes may disrupt many aspects of development, including sexual development before birth and at puberty, and are responsible for the common signs and symptoms of Klinefelter syndrome. Researchers are working to determine which genes contribute to the specific developmental and physical differences that can occur with Klinefelter syndrome.

Some people with features of Klinefelter syndrome have an extra X chromosome in only some of their cells; other cells typically have one X and one Y chromosome. (Rarely, other cells may have additional chromosome abnormalities.) In these individuals, the condition is described as mosaic Klinefelter syndrome (46,XY/47,XXY). It is thought that less than 10 percent of individuals with Klinefelter syndrome have the mosaic form. Boys and men with mosaic Klinefelter syndrome may have milder signs and symptoms than those with the extra X chromosome in all of their cells, depending on what proportion of cells have the additional chromosome.

Several conditions resulting from the presence of more than one extra sex chromosome in each cell are sometimes described as variants of Klinefelter syndrome. These conditions include 48,XXXY syndrome, 48,XXYY syndrome, and 49,XXXXY syndrome. Like Klinefelter syndrome, these conditions affect male sexual development and can be associated with learning disabilities and problems with speech and language development. However, the features of these disorders tend to be more severe than those of Klinefelter syndrome and affect more parts of the body. As doctors and researchers have learned more about the differences between these sex chromosome disorders, they have started to consider them as separate conditions.

Inheritance

Klinefelter syndrome is not inherited; the addition of an extra X chromosome occurs during the formation of reproductive cells (eggs or sperm) in one of an affected person's parents. During cell division, an error called nondisjunction prevents X chromosomes from being distributed normally among reproductive cells as they form. Typically, as cells divide, each egg cell gets a single X chromosome, and each sperm cell gets either an X chromosome or a Y chromosome. However, because of nondisjunction, an egg cell or a sperm cell can also end up with an extra copy of the X chromosome.

If an egg cell with an extra X chromosome (XX) is fertilized by a sperm cell with one Y chromosome, the resulting child will have Klinefelter syndrome. Similarly, if a sperm cell with both an X chromosome and a Y chromosome (XY) fertilizes an egg cell with a single X chromosome, the resulting child will have Klinefelter syndrome.

Mosaic Klinefelter syndrome (46,XY/47,XXY) is also not inherited. It occurs as a random error during cell division early in fetal development. As a result, some of the body's cells have the usual one X chromosome and one Y chromosome (46,XY), and other cells have an extra copy of the X chromosome (47,XXY).

Other Names for This Condition

47,XXY syndrome

Klinefelter syndrome (KS)

Klinefelter's syndrome

XXY syndrome

XXY trisomy

Additional Information & Resources

Genetic Testing Information

Genetic and Rare Diseases Information Center

Patient Support and Advocacy Resources

Research Studies from ClinicalTrials.gov

Scientific Articles on PubMed

References

Boada R, Janusz J, Hutaff-Lee C, Tartaglia N. The cognitive phenotype in Klinefelter syndrome: a review of the literature including genetic and hormonal factors. Dev Disabil Res Rev. 2009;15(4):284-94. doi: 10.1002/ddrr.83. Citation on PubMed or Free article on PubMed Central

Davis S, Howell S, Wilson R, Tanda T, Ross J, Zeitler P, Tartaglia N. Advances in the Interdisciplinary Care of Children with Klinefelter Syndrome. Adv Pediatr. 2016 Aug;63(1):15-46. doi: 10.1016/j.yapd.2016.04.020. No abstract available. Citation on PubMed or Free article on PubMed Central

Fruhmesser A, Kotzot D. Chromosomal variants in klinefelter syndrome. Sex Dev. 2011;5(3):109-23. doi: 10.1159/000327324. Epub 2011 Apr 29. Citation on PubMed

Giltay JC, Maiburg MC. Klinefelter syndrome: clinical and molecular aspects. Expert Rev Mol Diagn. 2010 Sep;10(6):765-76. doi: 10.1586/erm.10.63. Citation on PubMed

Groth KA, Skakkebaek A, Host C, Gravholt CH, Bojesen A. Clinical review: Klinefelter syndrome--a clinical update. J Clin Endocrinol Metab. 2013 Jan;98(1):20-30. doi: 10.1210/jc.2012-2382. Epub 2012 Nov 1. Citation on PubMed

Herlihy AS, Gillam L. Thinking outside the square: considering gender in Klinefelter syndrome and 47, XXY. Int J Androl. 2011 Oct;34(5 Pt 2):e348-9. doi: 10.1111/j.1365-2605.2010.01132.x. Epub 2011 Mar 31. No abstract available. Citation on PubMed

Nieschlag E, Ferlin A, Gravholt CH, Gromoll J, Kohler B, Lejeune H, Rogol AD, Wistuba J. The Klinefelter syndrome: current management and research challenges. Andrology. 2016 May;4(3):545-9. doi: 10.1111/andr.12208. No abstract available. Citation on PubMed

Nieschlag E. Klinefelter syndrome: the commonest form of hypogonadism, but often overlooked or untreated. Dtsch Arztebl Int. 2013 May;110(20):347-53. doi: 10.3238/arztebl.2013.0347. Epub 2013 May 17. Citation on PubMed or Free article on PubMed Central

Radicioni AF, Ferlin A, Balercia G, Pasquali D, Vignozzi L, Maggi M, Foresta C, Lenzi A. Consensus statement on diagnosis and clinical management of Klinefelter syndrome. J Endocrinol Invest. 2010 Dec;33(11):839-50. doi: 10.1007/BF03350351. Citation on PubMed

Sokol RZ. It's not all about the testes: medical issues in Klinefelter patients. Fertil Steril. 2012 Aug;98(2):261-5. doi: 10.1016/j.fertnstert.2012.05.026. Epub 2012 Jun 15. Citation on PubMed

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To use the sharing features on this page, please enable JavaScript. Klinefelter syndrome is a chromosomal condition in boys and men that can affect physical and intellectual development. Most commonly, affected individuals are taller than average are unable to father biological children (infertile); however the signs and symptoms of Klinefelter syndrome vary among boys and men with this condition.

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What causes Klinefelter Syndrome is when a male is born with an extra X chromosome. This is often diagnosed when the male is in adulthood.

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Overview

Klinefelter syndrome is a genetic condition that results when a boy is born with an extra copy of the X chromosome. Klinefelter syndrome is a genetic condition affecting males, and it often isn't diagnosed until adulthood.

Klinefelter syndrome may adversely affect testicular growth, resulting in smaller than normal testicles, which can lead to lower production of testosterone. The syndrome may also cause reduced muscle mass, reduced body and facial hair, and enlarged breast tissue. The effects of Klinefelter syndrome vary, and not everyone has the same signs and symptoms.

Most men with Klinefelter syndrome produce little or no sperm, but assisted reproductive procedures may make it possible for some men with Klinefelter syndrome to father children.

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Symptoms

Signs and symptoms of Klinefelter syndrome vary widely among males with the disorder. Many boys with Klinefelter syndrome show few or only mild signs. The condition may go undiagnosed until adulthood or it may never be diagnosed. For others, the condition has a noticeable effect on growth or appearance.

Signs and symptoms of Klinefelter syndrome also vary by age.

Babies

Signs and symptoms may include:

Weak muscles

Slow motor development - taking longer than average to sit up, crawl and walk

Delay in speaking

Problems at birth, such as testicles that haven't descended into the scrotum

Boys and teenagers

Signs and symptoms may include:

Taller than average stature

Longer legs, shorter torso and broader hips compared with other boys

Absent, delayed or incomplete puberty

After puberty, less muscle and less facial and body hair compared with other teens

Small, firm testicles

Small penis

Enlarged breast tissue (gynecomastia)

Weak bones

Low energy levels

Tendency to be shy and sensitive

Difficulty expressing thoughts and feelings or socializing

Problems with reading, writing, spelling or math

Men

Signs and symptoms may include:

Low sperm count or no sperm

Small testicles and penis

Low sex drive

Taller than average height

Weak bones

Decreased facial and body hair

Less muscular compared with other men

Enlarged breast tissue

Increased belly fat

When to see a doctor

See a doctor if you or your son has:

Slow development during infancy or boyhood. Delays in growth and development can be the first sign of a number of conditions that need treatment - including Klinefelter syndrome. Though some variation in physical and mental development is normal, it's best to check with a doctor if you have any concerns.

Male infertility. Many men with Klinefelter syndrome aren't diagnosed with infertility until they realize they're unable to father a child.

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Causes

Klinefelter syndrome occurs as a result of a random error that causes a male to be born with an extra sex chromosome. It isn't an inherited condition.

Humans have 46 chromosomes, including two sex chromosomes that determine a person's sex. Females have two X sex chromosomes (XX). Males have an X and a Y sex chromosome (XY).

Klinefelter syndrome can be caused by:

One extra copy of the X chromosome in each cell (XXY), the most common cause

An extra X chromosome in some of the cells (mosaic Klinefelter syndrome), with fewer symptoms

More than one extra copy of the X chromosome, which is rare and results in a severe form

Extra copies of genes on the X chromosome can interfere with male sexual development and fertility.

Risk factors

Klinefelter syndrome stems from a random genetic event. The risk of Klinefelter syndrome isn't increased by anything a parent does or doesn't do. For older mothers, the risk is higher but only slightly.

Complications

Klinefelter syndrome may increase the risk of:

Anxiety and depression

Social, emotional and behavioral problems, such as low self-esteem, emotional immaturity and impulsiveness

Infertility and problems with sexual function

Weak bones (osteoporosis)

Heart and blood vessel disease

Breast cancer and certain other cancers

Lung disease

Metabolic syndrome, which includes type 2 diabetes, high blood pressure (hypertension), and high cholesterol and triglycerides (hyperlipidemia)

Autoimmune disorders such as lupus and rheumatoid arthritis

Tooth and oral problems that make dental cavities more likely

Autism spectrum disorder

A number of complications caused by Klinefelter syndrome are related to low testosterone (hypogonadism). Testosterone replacement therapy reduces the risk of certain health problems, especially when therapy is started at the beginning of puberty.

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Klinefelter syndrome - Symptoms and causes

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Klinefelter syndrome is a genetic condition that results when a boy is born with an extra copy of the X chromosome. Klinefelter syndrome is a genetic condition affecting males, and it often isn't diagnosed until adulthood. Klinefelter syndrome may adversely affect testicular growth, resulting in smaller than normal testicles, which can lead to lower production of testosterone.