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This condition does not meet the definition of a rare disease in the U.S. (fewer than 200,000 Americans). There may be forms of this condition that are rare. NORD posts this report because limited information is available about this condition and it may be underdiagnosed.
Last updated:
3/29/2024
Years published: 1986, 1990, 1993, 1998, 1999, 2007, 2008, 2011, 2014, 2017, 2020, 2024
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, and Gioconda Alyea, Brazilian MD, MS, National Organization for Rare Disorders for assistance in the preparation of this report.
Summary
47,XXY (Klinefelter syndrome) is a chromosomal variation in males where one extra X chromosome is present which then results in a 47,XXY. 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 hormonal treatment care. With proper treatment, gynecomastia typically occurs in less than 10% of boys with 47,XXY (KS).
There is great variability to the neurodevelopmental profile in boys with 47,XXY (KS). Common cognitive and behavioral features may include speech and language delays, anxiety, ADHD (inattentive subtype) and emotional and social functioning challenges without treatment. 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 along with an evaluation by a pediatric endocrinologist familiar with 47,XXY (KS).
Introduction
Klinefelter syndrome is named after Dr. Henry Klinefelter, who identified the condition in the 1940s.
47,XXY is not rare and occurs 1 in 500 male births, however only about 25% of boys with 47, XXY (KS) are diagnosed and this diagnosis usually occurs in adulthood (Gravholt et al., 2018). Conditions that are variants of KS including mosaic karyotypes such as 46,XY/47,XXY and other conditions such as 48,XXYY, 48,XXXY and 49,XXXXY (poly-X Klinefelter syndromes) are rare.
Most newborn babies with KS have no significant or unusual features.
Most people with KS are identified though prenatal diagnosis or when the child does not progress through puberty completely or adequately.
Signs and symptoms noticeable in infants and young children may include:
With a decrease in androgen production, secondary sexual characteristics do not develop completely and the signs and symptoms in teenagers may include:
Many males with KS are not identified until they have low fertility problems as adults. Males with KS may have a relatively increased risk to develop breast cancer but not until after 60 years of age.
Other signs and symptoms may include:
Klinefelter syndrome is a sex chromosome disorder in individuals who were assigned male at birth 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 typically have two X chromosomes (46,XX), and males typically have one X and one Y chromosome (46,XY).
Most often, in almost 90% of cases, people with Klinefelter syndrome have the usual X and Y chromosomes, and one extra X chromosome, for a total of 47 chromosomes (47,XXY).
About 10% of the people diagnosed with Klinefelter syndrome have an extra X chromosome in only some of their cells, while the other cells have one X and one Y chromosome. These people are described as having mosaic Klinefelter syndrome (46,XY/47,XXY). People with mosaic Klinefelter syndrome may have (but not always) milder signs and symptoms than those with the extra X chromosome in all their cells, depending on what proportion of cells have the additional chromosome.
About 1% of the cases diagnosed as Klinefelter syndrome are caused by the presence of more than one extra sex chromosome in each cell are described as poly-X Klinefelter syndrome. These conditions include 48,XXXY syndrome, 48,XXYY syndrome and 49,XXXXY syndrome. The features of these conditions tend to be more severe than those of 46,XXY 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 classify them as separate conditions. The overall severity of the associated signs and symptoms appears to be related to the amount of additional X chromosome material present. For additional information please see the section on similar disorders below.
The X chromosome carries genes that have a role in many organ systems, playing a part, for example, in testes function, brain development and growth so consequences of an extra X chromosome include hypogonadism, gynecomastia and psychosocial behavioral concerns.
One of the genes located in the X chromosome, the androgen receptor (AR) gene encodes the androgen receptor. The AR gene provides instructions for making a protein called an androgen receptor. Androgens are hormones (such as testosterone) that are important for normal male sexual development before birth and during puberty. Androgen receptors allow the body to respond appropriately to these hormones.
The receptors are present in many of the body’s tissues, where they attach (bind) to androgens. The resulting androgen-receptor complex then binds to DNA and regulates the activity of androgen-responsive genes. By turning the genes on or off as necessary, the androgen receptor helps direct the development of male sexual characteristics. Androgens and androgen receptors also have other important functions in both males and females, such as regulating hair growth and sex drive.
In one region of the AR gene, a DNA segment known as CAG is repeated multiple times. This CAG segment is called a triplet or trinucleotide repeat. In most people, the number of CAG repeats in the AR gene ranges from fewer than 10 to about 36. The length of this CAG repeat is inversely correlated with the functional response of the androgen receptor to androgens. Thus, a short AR CAG repeat sequence correlates with a marked effect of androgens.
In people with Klinefelter syndrome, the X chromosome with the shortest AR CAG repeat has been demonstrated to be preferentially inactivated; this process is called skewed or nonrandom X-chromosome inactivation.
As the number of extra X chromosomes increases, physical and intellectual development are more likely to be affected. Skeletal, heart and vascular abnormalities can become very severe.
All major areas of development, including expressive and receptive language and coordination, are affected by extra X chromosome material.
Gonadal development is more affected with each additional X chromosome, leading to androgen deficiency.
Klinefelter syndrome is not inherited. Males with 47,XXY 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 (meiotic nondisjunction). Mosaic 47,XXY occurs because of an error in the division of the sex chromosomes in the zygote after fertilization (post-zygotic nondisjunction). The risk of having another affected child after having a child with KS is not increased above that of the general population. There is no evidence to suggest that a chromosomal nondisjunction process is likely to repeat in a particular family.
47,XXY (KS) is the most common human sex chromosome disorder, and it 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.
47,XXY is not rare, but it is seldom detected and diagnosed. Only about 25% of boys with KS are diagnosed, and this diagnosis usually occurs in adulthood (Gravholt et al., 2018).
Males with 47,XXY (KS) may be 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 or blood sample to detect abnormalities of chromosome numbers and provide a definitive diagnosis. 47,XXY (KS) can also be diagnosed prenatally through chorionic villous sampling (CVS) or amniotic fluid cells. Cell-Free DNA (cfDNA) is a new screening test available that detects if a fetus is high risk for 47,XXY (KS). However, the diagnosis should be confirmed via CVS, amniocentesis, or with CMA after birth. It is advisable to confirm the diagnosis since the cfDNA only identifies one additional X and cannot detect children with 48, XXXY or 49, XXXXY.
Treatment
One of the hallmarks of 47,XXY or 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. EHT is associated with improvements in multiple developmental areas.
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), and late diagnosis 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 among individuals.
For both 48,XXXY and 49,XXXXY early hormone treatment (EHT) is a treatment option that involves testosterone injections during infancy to assist with typical development. Depending on development, injections can also occur around five years of age and at the start of puberty. However, testosterone should be administered based upon an evaluation with a pediatric endocrinologist familiar with 48,XXXY and 49,XXXXY (Carey et al., 2021, ch.35).
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 sometimes 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. Social skills training classes may be beneficial.
Men with 47,XXY (KS) have low fertility. 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 (TESE) and intracytoplasmic sperm injection (ICSI) directly into an ovum is a medical technology available to assist men with 47,XXY (KS) father children.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government website.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
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Email: prpl@cc.nih.gov
Some current clinical trials also are posted on the following page on the NORD website:https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact: www.centerwatch.com
For information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
TEXTBOOKS
Carey J, Battaglia A, Viskochil D, & Cassidy S.Ch. 35, 47,XXY (Klinefelter Syndrome) and Related X and Y Chromosomal Conditions. Management of genetic syndromes (4th ed.). 539-562. John Wiley & Sons, 2021.
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 C, Lasutschinkow PC, Mitchell F, et al. 49,XXXXY syndrome: A study of neurological function in this uncommon X and Y chromosomal disorder. Am J Med Genet A. 2021;185(12):3557-3566. doi:10.1002/ajmg.a.61742
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, MS and Paduch, DA., 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.
Frühmesser A, Kotzot D. Chromosomal variants in Klinefelter syndrome. Sex Dev. 2011;5(3):109-123. doi:10.1159/000327324
Samango-Sprouse CA. Expansion of the phenotypic profile of the young child with XXY. Pediatr Endocrinol Rev. 2010;8 Suppl 1:160-8.
Visootsak J, Graham JM Jr. Social function in multiple X and Y chromosome disorders: XXY, XYY, XXYY, XXXY. Dev Disabil Res Rev. 2009;15(4):328-332. doi:10.1002/ddrr.76
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.
INTERNET
Defendi G. Klinefelter Syndrome. Medscape. January 31, 2022. https://emedicine.medscape.com/article/945649-overview Accessed Feb 14, 2024.
Los E, Leslie SW, Ford GA. Klinefelter Syndrome. [Updated 2023 Nov 12]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK482314/ Accessed Feb 14, 2024.
48,XXXY Syndrome. (2018, September 1). MedlinePlus. https://medlineplus.gov/genetics/condition/48xxxy-syndrome/ Accessed March 12, 2024.
49,XXXXY Syndrome. (2018, September 1). MedlinePlus. https://medlineplus.gov/genetics/condition/49xxxxy-syndrome/ Accessed March 12, 2024.
48,XXXY Syndrome. Genetic and Rare Diseases Information Center (GARD). 48,XXXY syndrome – About the Disease – Genetic and Rare Diseases Information Center (nih.gov) Accessed March 12, 2024.
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