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Klinefelter Syndrome

This condition was first identified by Dr. Harry Klinefelter at the Massachusetts General Hospital in Boston. A report published he and his coworkers reported case studies on nine men who had enlarged breasts, sparse facial and body hair and an inability to produce sperm.

Now more appropriately referred to as XXY Male of XXY Male Syndrome, males born with this condition have an extra sex chromosome XXY instead of the usual genotype XY. It is associated with a 47XXY karyotype and statistically occurs in 1/500 newborns.

Clinical features

Klinefelter is occasionally associated with lymphatic blockage or fetal hydrops, which causes lymphedema, and thus is included in a discussion of developmental disorders of the lymphatics It is thus extremely important that the child with Klinefelter have be referred to a certified lymphedema therapist so that a treatment program can be initiated to control and manage the lymphedema.

Original symptoms included tall stature, long upper extremities, poor pubertal development, microorchidism, enlarged breasts, sparce facial and body hair, small testes and subsequent sterility.

Recent studies have expanded the original symptoms to include infertility, incomplete masculinization; feminine, or pear shaped, body and body hair distribution, decreased libido, osteoporosis, taurodontism, venous disease (which may include mitral valve prolapse, varicose veins and venous ulcers), learning and emotional disorders, autoimmune disorders, low energy and self esteem, communication difficulties, especially with expressive language, frustration-based outbursts, motor skills issue and developmental delays. Also, there is a 20 times increased risk for XXY males to develop breast cancer than non XXY males.


A chromosomal analysis (karyotype) is used to confirm the diagnosis. In this procedure, a small blood sample is drawn. White blood cells are then separated from the sample, mixed with tissue culture medium, incubated, and checked for chromosomal abnormalities, such as an extra X chromosome.

The chromosome analysis looks at a number of cells, usually at least 20, which allows for the diagnosis of genetic conditions in both the full and mosaic state. In some cases, low-level mosaicism may be missed. However, if mosaicism is suspected (based on hormone levels, sperm counts, or physical characteristics), additional cells can be analyzed from within the same blood draw.


For proper care and treatment early diagnosis is important. The treatment includes hormone therapy such as testosterone replacement. Other treatment aspects should include the psychosocial and emotional problems, needed treatment for physiological side affects and later on even genetic counseling. Pat

A Guide for XXY Males and Their Families

Is the prevalence of Klinefelter syndrome increasing?

Eur J Hum Genet. 2007 Nov

Morris JK, Alberman E, Scott C, Jacobs P. 1Centre for Environmental and Preventive Medicine, Wolfson Institute of Preventive Medicine, Barts and the London, Queen Mary's School of Medicine and Dentistry, Charterhouse Square, London EC1M 6BQ, UK.

The birth prevalence of sex chromosome trisomies (SCT), that is individuals with an XYY, XXY or XXX sex chromosome constitution, is traditionally based on six surveys of unselected newborns carried out in the 1960s and early 1970s. All three SCTs had a prevalence of 1 in 1000 same sex births. We re-examined these prevalences based on additional cytogenetic studies of newborn surveys, spontaneous abortions, perinatal deaths and prenatal diagnoses. The more recent newborn surveys suggest there has been an increase in the prevalence of XXYs, but not of the other two SCTs since the original newborn series. The prevalence of XXYs has risen from 1.09 to 1.72 per 1000 male births (P=0.023). We suggest that such an increase, in the absence of an increase in the prevalence of XXX, is unlikely to be due to increased maternal age. As XXY is the only chromosome abnormality known where a substantial proportion ( approximately 50%) arise as the result of non-disjunction at the first paternal meiotic division, we speculate that some factor may be interfering with pairing and/or recombination of the sex bivalent at the paternal MI division.European Journal of Human Genetics advance online publication, 14 November 2007; doi:10.1038/sj.ejhg.5201956.


A simple screening method for detection of Klinefelter syndrome and other X-chromosome aneuploidies based on copy number of the androgen receptor gene.

Mol Hum Reprod. 2007 Oct

Ottesen AM, Garn ID, Aksglaede L, Juul A, Rajpert-De Meyts E. Department of Growth and Reproduction, Juliane Marie Centre, Section GR-5064, The National University Hospital of Copenhagen, DK-2100 Copenhagen, Denmark.

Due to the high prevalence and variable phenotype of patients with Klinefelter syndrome, there is a need for a robust and rapid screening method allowing early diagnosis. Here, we report on the development and detailed clinical validation of a quantitative real-time PCR (qPCR)-based method of the copy number assessment of the androgen receptor (AR) gene, located to Xq11.2-q12. We analysed samples from 50 individuals, including a healthy male and female controls and patients with Klinefelter syndrome (47,XXY; 48,XXXY) (n = 28), mosaicisms (46,XX/47,XXY/48XXYY; 45,X/46,XY) (n = 3), other sex chromosome abnormalities (46,XX males; 47,XYY)(n = 4) and normal karyotypes (46,XY) (n = 13). The reference range for the AR-copy number was established as 0.8-1.2 for one copy and 1.7-2.3 for two copies. The qPCR results were within the reference range in 17/18 samples (94%) or 30/31 (97%) samples with one or two copies of the AR gene, respectively. None of the Klinefelter patients were misdiagnosed as having a karyotype with only one X-chromosome, and in none of the 46,XY males were two copies demonstrated. We systematically compared qPCR results with those obtained with another PCR-based method, the XIST-gene expression. The XIST-expression based assay was correct in only 29/36 samples (81%). Our findings demonstrated that the AR-qPCR technique is a simple and reliable screening method for diagnosis of patients with Klinefelter syndrome or other chromosomal disorders involving an aberrant number of X-chromosomes.

Oxford Journals

Klinefelter's syndrome and Prader-Willi syndrome: a rare combination.

Psychopathology 2007

Verhoeven WM, de Vries BB, Duffels SJ, Egger JI, Noordam C, Tuinier S. Vincent van Gogh Institute for Psychiatry, Venray, The Netherlands.

In this paper a review is presented of the rare combination of Klinefelter's syndrome and Prader-Willi syndrome (PWS) and a second case of this combination with a uniparental disomy (UPD) etiology of PWS is described. Patients outlined in all other 8 reports and the present case have a PWS phenotype. Virtually no information is available on the behavioral and psychopathological phenotype in this combination. The latter may be explained by the observation that psychiatric syndromes are especially prevalent in PWS patients with a UPD. It is concluded that instability in mood and behavior in this and other syndromes should be preferentially treated with mood stabilizing agents. Copyright © 2007 S. Karger AG, Basel.


Genital anomalies in Klinefelter's syndrome.

Horm Res. 2007

Lee YS, Cheng AW, Ahmed SF, Shaw NJ, Hughes IA. Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.

BACKGROUND/AIMS: Klinefelter's syndrome is characterized by progressive testicular failure causing aspermatogenesis and androgen deficiency. Klinefelter patients classically have complete male sex differentiation, and genital anomalies are generally not recognized as associated features of the syndrome.

METHODS: We reviewed the cases of Klinefelter's syndrome with genitalia abnormalities from the Cambridge Disorders of Sex Development Database, and also reviewed previous case reports of genital anomalies associated with Klinefelter's syndrome and its variants.

RESULTS: We present seven Klinefelter patients with abnormalities of the genitalia, ranging from mild anomalies (chordee) to moderate undervirilisation (bifid scrotum and perineal hypospadias). Two cases were true hermaphrodites with karyotypes 47,XXY and 47,XXY/46,XX respectively. Though androgen insensitivity has been postulated previously as a possible pathogenic mechanism, we demonstrated normal androgen binding in 3 cases in which this was studied. Review of other case reports revealed a range of mild-to-severe abnormalities as well as cases reported as sex reversal, testicular feminization, and true hermaphroditism.

CONCLUSION: Genital anomalies are not commonly observed in Klinefelter's syndrome. However, it is important to acknowledge the association, and recognize Klinefelter's syndrome as one of the causes of abnormal genitalia at birth. Copyright 2007 S. Karger AG, Basel.


Clinical, endocrinological, and epigenetic features of the 46,XX male syndrome, compared with 47,XXY Klinefelter patients.

J Clin Endocrinol Metab. 2007

Vorona E, Zitzmann M, Gromoll J, Schüring AN, Nieschlag E. Institute of Reproductive Medicine, University Clinics of Münster, D-48129 Münster, Germany.

CONTEXT: The 46,XX male syndrome represents a rare, poorly characterized form of male hypogonadism.

OBJECTIVE: The objective of the study was to distinguish the 46,XX male syndrome from the more frequent 47,XXY-Klinefelter syndrome in regard to clinical, hormonal, and epigenetic features.

DESIGN: This was a case-control study.

SETTING: The study was conducted at a university-based reproductive medicine and andrology institution. PATIENTS: Eleven SRY-positive 46,XX males were compared with age-matched controls: 101 47,XXY Klinefelter patients, 78 healthy men, and 157 healthy women [latter all heterozygous for androgen receptor (AR) alleles]. INTERVENTIONS: There were no interventions.

MAIN OUTCOME MEASURES: There was a comparison of phenotype, endocrine profiles, and X-chromosomal inactivation patterns of AR alleles.

RESULTS: The 46,XX males were significantly smaller than Klinefelter patients or healthy men, resembling female controls in height and weight. The incidence of maldescended testes was significantly higher than that in Klinefelter patients and controls. Gynecomastia was more frequent in comparison with controls, whereas there was a nonsignificant trend in comparison with Klinefelter patients. All XX males were infertile and most were hypogonadal. The inactivation patterns of AR alleles in XX males were significantly more skewed than in Klinefelter patients and women. Seven of 10 heterozygous XX male patients displayed an extreme skewing of more than 80% with no preference toward the shorter or longer AR allele. The length of the AR CAG repeat polymorphism was positively related to traits of hypogonadism.

CONCLUSIONS: XX males are distinctly different from Klinefelter patients in terms of clinical and epigenetic features. Nonrandom X chromosome inactivation ratios are common in XX males, possibly due to the translocated SRY gene. The existence of a Y-chromosomal, growth-related gene is discussed.

Clinical Endocrinology and Metabolism

Additional Resources for Klinefelter Syndrome

Klinefelter Syndrome & Associates, Inc. PO Box 119 Roseville, CA 95678-0119 Phone: 916.773.1449 Fax: 916.773.1449


Web site: (Japenese version) [Note: group name may change to X & Y Family Genetic Network and include XXX, and XXY and the multiple sex chromosome variants]

Resources for families Introductory video about XXY, by mother whose son has Klinefelter Syndrome The Even Exchange, Newsletter

American Association for Klinefelter Syndrome Information and Support (AAKSIS)

Klinefelter Syndrome Support Group

Numerous links to other organizations and resources, created by an adult with Klinefelter Syndrome, regional groups, varients, international groups International Groups

Klinefelter Syndrome – A personal and Professional Guide

Australia Klinefelter Resources

Australian Klinefelter Support Group 4 Victoria Rd Acquire Fields NEW 02564 AUSTRALIA 02-605-2837

Victoria Support Group 41 Jesmond Rd Cordon, Victoria 03136 AUSTRALIA 03-9723-6148

Klinefelter Syndrome Support Group P.O.Box 3 Glendenning Mail Center NEW 2761 AUSTRALIA 02-9628-4142

Canada Klinefelter Resources

Canada Klinefelter Support Group Apt. 3, 2867 Young St. Toronto, ON. Canada M4N 2J5 416. 481.3171

Klinefelter's Syndrome Association

56 Little Yeldham Road Little Yeldham, Halstead, Essex CO9 4QT

Klinefelter Organisation

formerly the Klinefelter's Syndrome Club UK (KSCUK)

Belgium Klinefelter Resources

Belgische vereniging voor het syndroom van Klinefelter

Sweden and Denmark Klinefelter Resources

Swedish Klinefelter Association (Svenska XXY& Klinefelterföreningen)

Klinefelter Syndrome Booklets

Danish version or English version, The Turner Center

Norwegian Klinefelter Site

Pacific Northwest Regional Genetics Group

Klinefelter Syndrome

Klinefelter Syndrome Ohio Support Network

Misleading information in early Klinefelter studies

What is XXY? Hambley, (french version) XYY individual's sites Klinefelter’s Syndrome pamphlet and The X-tra Special Boy and For Boys Only, A Supplement pamphlets, by D Plumridge,C Brackets, and S LaFranchi, $3.50 for the main pamphlet and $1.25 for the supplement. Attn: CDRC Publications, Oregon Health Sciences University, CDRC, P.O. Box 574, Portland, Oregon 97207, Phone: (503) 279-8342 - checks to: Child Development & Rehabilitation Center.

Klinefelter Syndrome NIH

Klinefelter syndrome, also known as the XXY condition, is a term used to describe males who have an extra X chromosome in most of their cells. Instead of having the usual XY chromosome pattern that most males have, these men have an XXY pattern. Klinefelter syndrome is named after Dr. Henry Klinefelter, who first described a group of symptoms found in some men with the extra X chromosome. Even though all men with Klinefelter syndrome have the extra X chromosome, not every XXY male has all of those symptoms.

ICD Codes

ICD-10 Q98.0-Q98.4

ICD-9 758.7

External Links

Klinefelter Syndrome

Author: Harold Chen, MD, MS, FAAP, FACMG, Chief, Professor, Department of Pediatrics, Section of Perinatal Genetics, Louisiana State University Medical Center

Klinefelter Syndrome?

Or is he XXY? There IS a difference! A Parent's View

Understanding Klinefelter Syndrome

Klinefelter's Syndrome


Klinefelter Organization


Effects of varying lengths of synthetic speech output on augmented requesting and natural speech production in an adolescent with klinefelter syndrome.

2011 Sep


Genotype and phenotype in Klinefelter syndrome - impact of androgen receptor polymorphism and skewed X inactivation

2011 Oct 7


A Case Report of Fibular Aplasia, Tibial Campomelia, and Oligosyndactyly (FATCO) Syndrome Associated With Klinefelter Syndrome and Review of the Literature.

Infertility treatment in Klinefelter syndrome

Klinefelter syndrome: spermatogenesis and quality of gametes

Prevalence and psychosocial correlates of depressive symptoms among adolescents and adults with Klinefelter syndrome.

Further Evidence of the Clinical, Hormonal and Genetic Heterogeneity of Klinefelter Syndrome: A study of 216 Infertile Egyptian Patients.

Lymphedema People Internal Links

Lymphedema People Resources

klinefelter_syndrome.txt · Last modified: 2012/10/16 14:40 (external edit)