XXY (Klinefelter) Syndrome

Overview

Klinefelter syndrome is caused by an extra X chromosome in each cell, changing the typical male karyotype (46,XY) to 47,XXY. Klinefelter syndrome is characterized by testosterone deficiency (hypogonadism) and infertility. Additionally, affected males can present with a wide variety of physical, language, and social development involvement. In terms of management, if testosterone measures low for age in adolescents, regular treatments with testosterone are usually initiated. Affected children with XXY syndrome may require academic, social, and emotional support.

Historically, XXY syndrome was called Klinefelter syndrome, which involves a constellation of physical and behavioral characteristics that was first associated with the chromosome complement of XXY by Dr. Harry Klinefelter in the 1940s. With time, many males were found to have the XXY chromosome pattern but not the physical and behavioral phenotypes – it is estimated that only about 25% of men with XXY are ever diagnosed. [Samango-Sprouse: 2019] In In addition to the most typical XXY karyotype, other chromosome abnormalities may lead to a similar presentation. These include XY/XXY mosaicism, where a percentage of cells are normal (46,XY), and a percentage have an extra X chromosome (47,XXY). Individuals with mosaicism may still be fertile, depending on the percentage and distribution of normal XY cells. Although less common, it is also possible to have more than 1 extra X chromosome (e.g., 48,XXXY), which is typically associated with a more severe phenotype and intellectual disability.

Other Names & Coding

47,XXY
Sex chromosome aneuploidy
XXY condition
ICD-10 coding

Q98.0, Klinefelter syndrome karyotype 47,XXY

Q98.1, Klinefelter syndrome, male with more than 2 X chromosomes

Q98.4, Klinefelter syndrome, unspecified

ICD-10 for Klinefelter Syndrome provides further coding details.

Prevalence

XXY syndrome is the most common disorder of sex chromosomes, affecting approximately 1:1,000 males. [Morris: 2008] Variants are rarer; 48,XXXY is present in 1:170,000–1:50,000 male births. [Visootsak: 2006]

Genetics

Boys with XXY syndrome inherit an extra X chromosome from either their mother or father during formation of the egg or sperm. About half of the cases are from maternal chromosomes, half from paternal chromosomes. This is a chance occurrence; families with 1 member who has XXY syndrome are not at higher risk of other affected family members. Mosaic Klinefelter syndrome (46,XY /47,XXY) usually occurs as an error in cell division after conception in a developing embryo.

Prognosis

Although the range of features is wide, most individuals with XXY will lead normal lives with a normal life expectancy. Boys diagnosed early and who have received developmental therapies, educational interventions, social support, and testosterone therapy are likely to have better outcomes.

Practice Guidelines

Although there are no formal guidelines, the following provides an updated review of Klinefelter syndrome, including causes, diagnostic strategies, and management.

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. PubMed abstract / Full Text

Roles of the Medical Home

The medical home provider will need to monitor maturation, response to testosterone therapy, developmental and educational progress, and patient and family adjustment. When the diagnosis occurs prenatally, it is important to counsel families that reports of developmental and behavioral problems associated with the condition are affected by selection bias since individuals without developmental problems would not usually be offered genetic testing.

Clinical Assessment

Overview

Many men are diagnosed when, in the midst of leading normal lives, they have a karyotype or chromosome study as part of the workup for infertility. Approximately 25% of patients are diagnosed during childhood as part of an evaluation of developmental delay, hypotonia, abnormal behaviors, hypogonadism, and/or gynecomastia via chromosomal testing. The condition is rarely identified on prenatal chromosome analysis (approximately 10% of cases); however, this may change with further implementation of non-invasive prenatal screening (NIPS), which is becoming more accessible for prenatal detection of aneuploidies.

XXY syndrome should be considered in infants and children with developmental delay or in adolescent males who are tall, overweight with fat distributed in a pear-shaped pattern, and have decreased secondary sexual characteristics in puberty, gynecomastia, and learning problems.

Screening

Of Family Members

Since this condition typically does not run in families, screening of family members is not recommended.

Presentations

Characteristics of individuals with XXY syndrome evolve with developmental stage:
  • Infants may be described as "easy" babies. They may present with hypotonia and show developmental delays in some or all areas (particularly language).
  • Toddlers may have continued language delays, or they may be diagnosed with sensory integration disorder, auditory processing problems, and autism spectrum disorder.
  • Young boys and teens with XXY syndrome may be taller and less muscular than their male peers.
  • Adolescents may experience normal or delayed puberty but have decreased facial and body hair; smaller, firmer testicles; decreased muscle development; and gynecomastia. Depression and anxiety may occur at this age; aggressive or oppositional behaviors may also be seen. If hypogonadism is left untreated, affected individuals develop a eunuchoid body habitus, with small testes, gynecomastia, and increased levels of gonadotropins.
  • Older teens and adults may not look different from other males their age, except possibly taller. Low levels of testosterone can cause infertility despite normal sexual function and a high-pitched voice. Osteoporosis is often found in older teens and adults with XXY syndrome.
Other presentations may include:
  • Hand tremors
  • Decreased activity and endurance level
  • Sleep abnormalities
  • Difficulties in social situations (shy, immature, passive) with low self-esteem
  • Learning problems
  • Expressive greater than receptive language problems
  • Decreased auditory recall
  • Easily frustrated
  • Higher risk of autoimmune diseases in adults
  • Joint laxity

Diagnostic Criteria

Diagnosis is made by karyotype or chromosomal microarray studies.

Differential Diagnosis

Hypogonadotropic hypogonadism: Males with hypogonadotropic hypogonadism have low testosterone due to a failure of gonadotropin release. Hypogonadotropic hypogonadism can be acquired (e.g., secondary to brain trauma) or congenital. Examples of the latter include Kallmann syndrome (hypogonadotropic hypogonadism and anosmia) and idiopathic hypogonadotropic hypogonadism. In these individuals, the gonadotropins luteinizing hormone (LH) and follicle-stimulating hormone (FSH) are low, whereas in individuals with XXY syndrome, they are high. Karyotype results will identify those with XXY syndrome. See Hypogonadotropic Hypogonadism (GeneReviews) for more information.

Fragile X syndrome: Those with fragile X may have some of the same physical characteristics that those with XXY have, including intellectual disability, autistic features, hypotonia, and tall stature. The 2 conditions may seem more similar in younger children; in general, they can be distinguished much more easily in older children and adolescents. They can be differentiated definitively by genetic testing, which will demonstrate sex chromosome aneuploidy in individuals with XXY. The Portal’s module on Fragile X Syndrome provides further diagnostic and management information.

Marfan syndrome: Individuals with Marfan syndrome, a connective tissue disorder, are tall of stature and may demonstrate hypotonia. Karyotyping will identify males with the XXY syndrome; Marfan syndrome is a clinical or molecular diagnosis based on family history and affected body systems. It is sometimes confirmed with genetic testing for mutations in the FBN1 gene. See Marfan Syndrome (GeneReviews) for more information.

Other overlapping conditions: Especially in younger children, XXY syndrome has a nonspecific presentation that overlaps with many other genetic conditions, including microdeletion and microduplication syndromes, metabolic disorders such as homocystinuria, and overgrowth disorders such as Sotos syndrome. If routine chromosome studies are normal in a child with features of XXY syndrome, refer for genetic evaluation.

History & Examination

Current & Past Medical History

No significant associations; hypotonia may be a feature

Family History

No family history is expected; XXY syndrome usually occurs sporadically or randomly.

Pregnancy/Perinatal History

Pregnancy/perinatal course is not affected.

Developmental & Educational Progress

Children with XXY syndrome may have developmental delays, especially in language development. School performance may be poor, specifically in language, and attention problems may be present. [Ross: 2008] Monitor developmental and educational progress and ensure that adequate therapies are in place.

Maturational Progress

Maturation usually begins normally, but unless the individual is receiving testosterone replacement/supplementation, facial and body hair and the expected increase in muscle mass can fail to develop. Maturational progress with the onset of adolescence should be monitored closely by a pediatric endocrinologist. Boys with XXY syndrome are sometimes diagnosed when puberty is delayed. [Zeger: 2008]

Social & Family Functioning

Individuals and their families may need help with adjusting to diagnosis. Boys with XXY may be withdrawn socially and need social skills training.

Physical Exam

General

Individuals with XXY syndrome may be quiet and have decreased interaction with the examiner.

Growth Parameters

Ht | Wt | BMI Boys are usually tall and may have abnormal body proportions with long legs and a shorter trunk. They can have decreased muscle mass and are often overweight. Weight and BMI should be monitored closely with preventative measures taken to avoid obesity.

HEENT/Oral

Example of taurodontism, which is enlargement of the body and shortening of the roots of the tooth
Look for abnormal teeth; teeth may often show taurodontism, which is enlargement of the body and shortening of the roots of the tooth. [Jayashankara: 2013] See photo right from [Jayashankara: 2013] for an example of taurodontism.

Enamel defects may also be present. [Ramasamy: 2009]

Chest

Routine breast examinations should be performed on adolescents with XXY syndrome.

Genitalia

Young boys may have a small penis and small firm testes even after adolescent maturation begins. Though uncommon, micropenis is sometimes seen in boys with XXY syndrome.

Neurologic Exam

Neurologic exam should be normal, yet hypotonia and a resting hand tremor are sometimes present. Although strength may be decreased in males with XXY syndrome, this is difficult to demonstrate on exam. [Ross: 2008]

Testing

Laboratory Testing

Testosterone, luteinizing hormone (LH), follicle-stimulating hormone (FSH) levels, estradiol, prolactin, and insulin-like growth factor (IGF) in the blood may be measured as a baseline and in response to treatment with testosterone. Before treatment, the testosterone level is usually low; LH and FSH levels are usually high.

Genetic Testing

Karyotyping will confirm the diagnosis of XXY syndrome. Typically, chromosomes from approximately 20 cells are counted in standard karyotyping, so a low percentage mosaicism may be missed. Additionally, a karyotype of blood cells reflects the karyotype in only 1 tissue.

Other Testing

Bone density screening should be performed on a regular basis starting in the teen years.

Specialty Collaborations & Other Services

Pediatric Genetics (see ID providers [4])

Consider a consultation for diagnostic testing and family education.

Developmental - Behavioral Pediatrics (see ID providers [2])

Consider for help in evaluating developmental and academic progress and suggesting therapies as needed.

Pediatric Endocrinology (see ID providers [2])

Consider referral for ongoing management of testosterone therapy.

Treatment & Management

Pearls & Alerts for Treatment & Management

Fertility treatments

Sperm extractions, in conjunction with testosterone therapy, have been used with success to allow fertility in men with XXY syndrome. The treatments are expensive and additional measures, such as intracytoplasmic sperm injection, may also be needed.

Systems

Endocrine/Metabolism

In most cases, testosterone is measured in adolescents with XXY syndrome. If low for age (not all teenage boys with XXY syndrome will have a low level), treatment is started with testosterone on a regular basis. Testosterone increases facial and body hair, muscle development, and sex drive; it may decrease gynecomastia and osteoporosis risk. Boys with XXY syndrome that are treated with testosterone tend to have higher self-esteem, perhaps because they fit in better with their peers. Attention and concentration may also be improved in these boys. Because low testosterone leads to release of the gonadotropins LH and FSH, these levels are high in untreated individuals with the XXY syndrome.

Treatment is usually initiated at 11 or 12 years of age with testosterone enanthate (Delatestryl) or cypionate (Depo-Testosterone) at 25-50 mg IM q 2 weeks–1 month. It is then increased gradually depending on the degree of virilization, growth, and serum gonadotropin levels, which should decrease with therapy to the high normal range. (Final adult dose is approximately 200 mg IM q 2–3 weeks.)

Once treatment starts, monitor for possible side effects including worsening acne, too rapid sexual development, prostate enlargement, and behavior problems–especially aggression. Transdermal methods of testosterone administration may also be used in older individuals with XXY syndrome.

Note that testosterone therapy does not change the rate of infertility. The option of semen collection and sperm-banking (cryopreservation) in XXY individuals during puberty may be discussed during visits to the geneticist or endocrinologist. Sperm is retrievable from about 50% of adolescents/young adults [Nahata: 2016] and from smaller proportions as individuals age.

Specialty Collaborations & Other Services

Pediatric Endocrinology (see ID providers [2])

Referral can be helpful for initiation and management of testosterone therapy. Referral to a reproductive specialist is often made by the pediatric endocrinologist and may be helpful in older adolescents and young adults.

Pediatric Urology (see ID providers [1])

Fertility questions may be addressed by urology.

Development (general)

Developmental delays present in about 25% of those with XXY syndrome and should prompt referral to developmental therapies (physical, occupational, and speech/language) as clinically indicated.

Specialty Collaborations & Other Services

Developmental - Behavioral Pediatrics (see ID providers [2])

May be helpful in the evaluation and management of developmental delays and behavioral and emotional challenges

Physical Therapy (see ID providers [34])

May be helpful for addressing gross motor delays and/or lack of abilities and coordination

Occupational Therapy, Pediatric (see ID providers [27])

May be helpful for fine motor delays and sensory integration problems

Speech - Language Pathologists (see ID providers [68])

May be helpful for the expressive language delay frequently seen in males with XXY syndrome

Learning/Education/Schools

School progress, including both academics and social functioning, should be monitored. If problems are evident, individuals with XXY syndrome should have a comprehensive psychoeducational profile. The medical home provider may need to help the family advocate appropriate educational resources based on this testing.

Specialty Collaborations & Other Services

Mental Health Evaluation/Assessment (see ID providers [35])

A full psychoeducational profile to identify strengths, weaknesses, and alternative teaching strategies may be helpful in males with XXY syndrome who are having difficulties in school.

Maturation/Sexual/Reproductive

Males with XXY syndrome are likely infertile and may need to use alternative methods to father children. They usually have normal sexual function and will need to be counseled as adolescents about the use of barrier methods for prevention of sexually transmitted diseases. Males with mosaic XXY syndrome may still be fertile and will need typical counseling for contraception.

Specialty Collaborations & Other Services

Pediatric Urology (see ID providers [1])

May be helpful in answering questions and managing infertility in males with XXY syndrome

Mental Health/Behavior

Affected individuals and their families may need help adjusting to this diagnosis. Some boys or young men will be concerned about the risk of infertility; it is important to validate and address this concern. Some boys will be embarrassed about having an “extra” X chromosome and may feel this makes them less male or partially female. However, XXY syndrome is not an intersex condition and does not lead to an increased likelihood for males to identify as females.

The personality and behavior of boys with XXY syndrome have been described as shy, reserved, sensitive, and passive in childhood, which, together with unattended learning difficulties, may lead to secondary adaptive and behavioral problems in adolescence. [Sørensen: 1992] [Ross: 2008] Testosterone treatment from puberty may assist in psychosocial adaption during adolescence. [Simm: 2006] [Maggi: 2007] Social skills training, special education services, or provisions in an individualized educational plan for learning problems may also help improve self-esteem. [Samango-Sprouse: 2002] Sometimes, having a diagnosis can help qualify children for services. More details about the personal impact of XXY syndrome and the influence of age at diagnosis, clinical, social, and demographic factors on adult quality of life outcomes can be found in [Herlihy: 2011].

Specialty Collaborations & Other Services

Developmental - Behavioral Pediatrics (see ID providers [2])

May be helpful for social skills training and behavioral problems

Family Counseling (see ID providers [69])

May help families and individuals adjust to diagnosis

General Counseling Services (see ID providers [206])

May be helpful in improving body image, self-esteem, mental health, and social supports

Transitions

Adult males with XXY syndrome have an increased risk of osteoporosis, breast cancer, extragonadal germ cell tumor, varicose veins, and lung disease. They also have an increased risk of autoimmune disease compared to the general population (including thyroiditis, lupus, and type 1 diabetes). Teens with XXY syndrome who are transitioning to adult care should be made aware of the symptoms of these conditions, and screening should be performed as necessary. The Portal's page on Transition Issues discusses the role of the medical home during this transition process and provides information to families about how to find a doctor who will meet the transitioning child's medical needs.
No Related Issues were found for this diagnosis.

Ask the Specialist

Should all boys with gynecomastia be tested for XXY syndrome?

Gynecomastia is common among adolescent boys. If puberty is otherwise proceeding normally, including normal testicular growth, XXY syndrome is unlikely.

Can I send testing for XXY syndrome, or does it need to be sent by a specialist?

A routine chromosome study can usually be sent from a primary care provider’s office. Most insurance companies require prior authorization for genetic testing.

Is a karyotype (G-banded chromosome study) or a microarray the best test for XXY syndrome?

It depends on how the patient presents. Either test will detect XXY syndrome. If you have a high concern for 47,XXY and don’t suspect another condition (as in a teenager with gynecomastia and small testes for Tanner stage), a karyotype will probably be sufficient. The microarray, though more expensive, is a more sensitive test for other chromosome abnormalities. It can be considered as a first step in boys with developmental delay or as a second step for children whose chromosome study is normal, but XXY is still suspected. Prior authorization may be needed for these tests.

Resources for Clinicians

On the Web

Klinefelter Syndrome (NORD)
Intended for families but with good introductory information for clinicians, too; National Organization for Rare Disorders.

Helpful Articles

PubMed search for XXY (Klinefelter) syndrome in children, last 3 years.

Bearelly P, Oates R.
Recent advances in managing and understanding Klinefelter syndrome.
F1000Res. 2019;8. PubMed abstract / Full Text
Review on the current standard of care in terms of management for patients with Klinefelter syndrome.

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. PubMed abstract / Full Text
Updated review of Klinefelter syndrome, including causes, diagnostic strategies and management

Shiraishi K, Matsuyama H.
Klinefelter syndrome: From pediatrics to geriatrics.
Reprod Med Biol. 2019;18(2):140-150. PubMed abstract / Full Text
Recommendations on how to transition patients with Klinefelter syndrome from pediatrics to adult care.

Resources for Patients & Families

Information on the Web

Klinefelter Syndrome (Genetics Home Reference)
Excellent, detailed review of condition for patients and families; U.S. National Library of Medicine.

XXY Syndrome (MedlinePlus)
Brief information about causes, symptoms, tests, treatment, possible complications, and support groups; U.S. National Library of Medicine.

Klinefelter Syndrome (GARD)
Information about cause, inheritance, treatment, and more of Klinefelter or XXY syndrome; Genetic and Rare Diseases Information Center.

National & Local Support

American Association for Klinefelter Syndrome Information and Support (AAKSIS)
Information, education, and support via toll-free telephone line, e-mail, network of support groups, and an annual educational conference.

Association for X and Y Variations (AXYS)
An organization founded by a mother of a child with Klinefelter syndrome that provides resources, research, and support for those affected by X and Y chromosome variations.

Services for Patients & Families in Idaho (ID)

For services not listed above, browse our Services categories or search our database.

* number of provider listings may vary by how states categorize services, whether providers are listed by organization or individual, how services are organized in the state, and other factors; Nationwide (NW) providers are generally limited to web-based services, provider locator services, and organizations that serve children from across the nation.

Authors & Reviewers

Initial publication: June 2015; last update/revision: February 2020
Current Authors and Reviewers:
Author: Josue Flores-Daboub, MD
Authoring history
2015: update: Sarah L. Dugan, MDR
2014: update: Karin Dent, MS, CGCA
2014: first version: Lynne M. Kerr, MD, PhDA
AAuthor; CAContributing Author; SASenior Author; RReviewer

Bibliography

Bearelly P, Oates R.
Recent advances in managing and understanding Klinefelter syndrome.
F1000Res. 2019;8. PubMed abstract / Full Text
Review on the current standard of care in terms of management for patients with Klinefelter syndrome.

Herlihy AS, McLachlan RI, Gillam L, Cock ML, Collins V, Halliday JL.
The psychosocial impact of Klinefelter syndrome and factors influencing quality of life.
Genet Med. 2011;13(7):632-42. PubMed abstract
Investigates the personal impact of Klinefelter syndrome and the influence of age at diagnosis, clinical, social, and demographic factors on adult quality of life outcomes.

Jayashankara C, Shivanna AK, Sridhara K, Kumar PS.
Taurodontism: A dental rarity.
J Oral Maxillofac Pathol. 2013;17(3):478. PubMed abstract / Full Text

Maggi M, Schulman C, Quinton R, Langham S, Uhl-Hochgraeber K.
The burden of testosterone deficiency syndrome in adult men: economic and quality-of-life impact.
J Sex Med. 2007;4(4 Pt 1):1056-69. PubMed abstract

Morris JK, Alberman E, Scott C, Jacobs P.
Is the prevalence of Klinefelter syndrome increasing?.
Eur J Hum Genet. 2008;16(2):163-70. PubMed abstract

Nahata L, Yu RN, Paltiel HJ, Chow JS, Logvinenko T, Rosoklija I, Cohen LE.
Sperm Retrieval in Adolescents and Young Adults with Klinefelter Syndrome: A Prospective, Pilot Study.
J Pediatr. 2016;170:260-5.e1-2. PubMed abstract

Ramasamy R, Ricci JA, Palermo GD, Gosden LV, Rosenwaks Z, Schlegel PN.
Successful fertility treatment for Klinefelter's syndrome.
J Urol. 2009;182(3):1108-13. PubMed abstract

Ross JL, Roeltgen DP, Stefanatos G, Benecke R, Zeger MP, Kushner H, Ramos P, Elder FF, Zinn AR.
Cognitive and motor development during childhood in boys with Klinefelter syndrome.
Am J Med Genet A. 2008;146A(6):708-19. PubMed abstract

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. PubMed abstract / Full Text
Updated review of Klinefelter syndrome, including causes, diagnostic strategies and management

Samango-Sprouse, C.
XXY: The Hidden Disability and a Prototype for an Infantile Presentation of Developmental Dyspraxia (IDD.
Infants Young Child. 2002(15):11-18. PubMed abstract

Shiraishi K, Matsuyama H.
Klinefelter syndrome: From pediatrics to geriatrics.
Reprod Med Biol. 2019;18(2):140-150. PubMed abstract / Full Text
Recommendations on how to transition patients with Klinefelter syndrome from pediatrics to adult care.

Simm PJ, Zacharin MR.
The psychosocial impact of Klinefelter syndrome--a 10 year review.
J Pediatr Endocrinol Metab. 2006;19(4):499-505. PubMed abstract

Sørensen K.
Physical and mental development of adolescent males with Klinefelter syndrome.
Horm Res. 1992;37 Suppl 3:55-61. PubMed abstract

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

Zeger MP, Zinn AR, Lahlou N, Ramos P, Kowal K, Samango-Sprouse C, Ross JL.
Effect of ascertainment and genetic features on the phenotype of Klinefelter syndrome.
J Pediatr. 2008;152(5):716-22. PubMed abstract