Definition and research guide
This page combines a MeSH definition, publication statistics and selected research abstracts. It is a starting point for reading the literature, not a medical textbook or a systematic evidence review.
Content available: 4 complete abstracts (696 words), 10 references. Full article text is not stored or reproduced here; follow the PMID, DOI or PMC links to read the original sources and their access terms.
Definition
A form of male hypogonadism, characterized by the presence of an extra X chromosome, small testes, seminiferous tubule dysgenesis, elevated levels of gonadotropins, low serum testosterone, underdeveloped secondary sex characteristics, and male infertility (infertility, MALE). Patients tend to have long legs and a slim, tall stature. gynecomastia is present in many of the patients. The classic form has the karyotype 47,XXY. Several karyotype variants include 48,XXYY; 48,XXXY; 49,xxxxy, and mosaic patterns ( 46,XY/47,XXY; 47,XXY/48,XXXY, etc.).
Definition: NLM Medical Subject Headings (MeSH) scope note (Public domain (U.S. National Library of Medicine); attribution requested). View the MeSH record.
Also known as: Klinefelter Syndromes; Syndrome, Klinefelter; Syndromes, Klinefelter; Klinefelter's Syndrome; Klinefelters Syndrome; Syndrome, Klinefelter's; XXY Syndrome; Syndromes, XXY.
Where it fits in the MeSH classification
- Broader topics
- Sex Chromosome Disorders of Sex Development; Hypogonadism
Related concepts
- Hypogonadism
- Chromosomes
- Testis
- Gonadotropins
- Testosterone
- Infertility
- Gynecomastia
- Xxxxy
Research landscape
PubMed indexes 4,258 records tagged with the MeSH heading “Klinefelter Syndrome” (counts retrieved 2026-10-29). 421 of them (9.9%) were published from 2020 onward, and the busiest period so far is through 1999 with 2,607 records.
Reviews account for 561 records (13.2%) and meta-analyses for 14. Randomized controlled trials number 9 (0.2%) as a share of all records on the topic. Randomized trials make up only a small share of this literature, so much of what is known comes from laboratory, observational or descriptive work.
Show the data
| Period | Records |
|---|---|
| through 1999 | 2,607 |
| 2000-2009 | 518 |
| 2010-2019 | 712 |
| 2020 onward | 421 |
Publication-type chart data
| Type | Records | Share |
|---|---|---|
| Reviews | 561 | 13.2% |
| Meta-analyses | 14 | 0.3% |
| Randomized controlled trials | 9 | 0.2% |
Method: PubMed query "Klinefelter Syndrome"[MeSH Terms] with publication-type and date filters, retrieved 2026-10-29.
Reading the evidence in rare and inherited diseases
Rare conditions are difficult to study: few patients means small studies, case reports and registries are common, and randomized trials are the exception. Small samples limit precision and can exaggerate effects, and cases reported in the literature may be the most severe or unusual. Evidence from many small studies is best read together. Check how patients were identified, how many were included and how long they were followed.
Evidence from open-access studies
These open-access studies come from PubMed’s best-match results for this heading (papers whose main topic it is), ranked here by citation count, with one recent addition. Each abstract is reproduced in full under its recorded open licence so that you can read the authors’ own words. They illustrate the literature; they are not a systematic summary of it. Citation counts measure attention, not reliability or clinical benefit.
| Study / authors | Year | Source label / design | Europe PMC citations | Licence / source |
|---|---|---|---|---|
| Klinefelter syndrome (KS): genetics, clinical phenotype and hypogonadism | 2017 | Review article Design not recorded in structured metadata | 206 | cc by PMID 27644703 · DOI · PMC5269463 |
| DNA hypermethylation and differential gene expression associated with Klinefelter syndrome | 2018 | Research article Design not recorded in structured metadata | 88 | cc by PMID 30213969 · DOI · PMC6137224 |
| Klinefelter syndrome as a window on the aetiology of language and communication impairments in children: the neuroligin-neurexin hypothesis | 2011 | Research article Design not recorded in structured metadata | 58 | cc by PMID 21418292 · DOI · PMC3107947 |
| Body Composition by DXA in Patients with Klinefelter and Kallmann Syndrome: The Kama Study | 2026 | Research article Design not recorded in structured metadata | 2 | cc by PMID 41073368 · DOI · PMC13016807 |
Klinefelter syndrome (KS): genetics, clinical phenotype and hypogonadism [1]
Abstract reading summary — source excerpts
- Opening excerpt
- Klinefelter Syndrome (KS) is characterized by an extreme heterogeneity in its clinical and genetic presentation.
- Closing excerpt
- The aim of this review is to provide an update on both genetic and clinical phenotype and their interrelationships.
- Interpretation limits
- Verbatim excerpts from the authors’ abstract; the closing excerpt may describe a finding, limitation or recommendation. Design, population, effect size and uncertainty have not been independently extracted or appraised. Read the complete abstract and linked paper before interpreting the findings.
Read complete abstract (97 words)
Klinefelter Syndrome (KS) is characterized by an extreme heterogeneity in its clinical and genetic presentation. The relationship between clinical phenotype and genetic background has been partially disclosed; nevertheless, physicians are aware that several aspects concerning this issue are far to be fully understood. By improving our knowledge on the role of some genetic aspects as well as on the KS, patients' interindividual differences in terms of health status will result in a better management of this chromosomal disease. The aim of this review is to provide an update on both genetic and clinical phenotype and their interrelationships.
Abstract reproduced from the open-access article under the recorded cc by licence; © the authors. PMID 27644703 · DOI · PMC5269463
DNA hypermethylation and differential gene expression associated with Klinefelter syndrome [2]
Abstract reading summary — source excerpts
- Opening excerpt
- Klinefelter syndrome (KS) has a prevalence ranging from 85 to 250 per 100.
- Closing excerpt
- Based on our data we point towards new candidate genes, which may be implicated in the phenotype and further point towards non-coding genes, which may be involved in X chromosome inactivation in KS.
- Interpretation limits
- Verbatim excerpts from the authors’ abstract; the closing excerpt may describe a finding, limitation or recommendation. Design, population, effect size and uncertainty have not been independently extracted or appraised. Read the complete abstract and linked paper before interpreting the findings.
Read complete abstract (200 words)
Klinefelter syndrome (KS) has a prevalence ranging from 85 to 250 per 100.000 newborn boys making it the most frequent sex chromosome aneuploidy in the general population. The molecular basis for the phenotypic traits and morbidity in KS are not clarified. We performed genome-wide DNA methylation profiling of leucocytes from peripheral blood samples from 67 KS patients, 67 male controls and 33 female controls, in addition to genome-wide RNA-sequencing profiling in a subset of 9 KS patients, 9 control males and 13 female controls. Characterization of the methylome as well as the transcriptome of both coding and non-coding genes identified a unique epigenetic and genetic landscape of both autosomal chromosomes as well as the X chromosome in KS. A subset of genes show significant correlation between methylation values and expression values. Gene set enrichment analysis of differentially methylated positions yielded terms associated with well-known comorbidities seen in KS. In addition, differentially expressed genes revealed enrichment for genes involved in the immune system, wnt-signaling pathway and neuron development. Based on our data we point towards new candidate genes, which may be implicated in the phenotype and further point towards non-coding genes, which may be involved in X chromosome inactivation in KS.
Abstract reproduced from the open-access article under the recorded cc by licence; © the authors. PMID 30213969 · DOI · PMC6137224
Klinefelter syndrome as a window on the aetiology of language and communication impairments in children: the neuroligin-neurexin hypothesis [3]
Abstract reading summary — source excerpts
- Opening excerpt
- AimTo compare the phenotype in Klinefelter syndrome (KS) with (i) specific language impairment (SLI) and (ii) XXX and XYY trisomies.
- Closing excerpt
- This speculative proposal demonstrates the potential of illuminating the aetiology of common neurodevelopmental disorders by studying children with SCTs.
- Interpretation limits
- Verbatim excerpts from the authors’ abstract; the closing excerpt may describe a finding, limitation or recommendation. Design, population, effect size and uncertainty have not been independently extracted or appraised. Read the complete abstract and linked paper before interpreting the findings.
Read complete abstract (186 words)
AimTo compare the phenotype in Klinefelter syndrome (KS) with (i) specific language impairment (SLI) and (ii) XXX and XYY trisomies.MethodsPhenotypes of KS, XXX and XYY were based on data from a systematic review of neurodevelopmental outcomes plus a recent parent survey. Phenotype of SLI was based on a published survey of children attending a special school.ResultsThere are close similarities between the KS phenotype and SLI. Furthermore, a minority of children with KS have features of autistic spectrum disorder. Similar language and communication problems are seen in the other two sex chromosome trisomies (SCTs), XXX and XYY.ConclusionWe propose the neurexin-neuroligin hypothesis, based on the observation that neuroligin genes, which occur on both X and Y chromosomes, are involved in the same synaptic networks as neurexin genes with common variants that affect risk for SLI and autism. According to our hypothesis, the effect of a triple dose of neuroligin gene product will be particularly detrimental when it occurs in conjunction with specific variants of neurexin genes on other chromosomes. This speculative proposal demonstrates the potential of illuminating the aetiology of common neurodevelopmental disorders by studying children with SCTs.
Abstract reproduced from the open-access article under the recorded cc by licence; © the authors. PMID 21418292 · DOI · PMC3107947
Body Composition by DXA in Patients with Klinefelter and Kallmann Syndrome: The Kama Study [4]
Abstract reading summary — source excerpts
- Opening excerpt
- ContextKlinefelter syndrome and Kallmann syndrome are 2 rare genetic disorders characterized by reduced testosterone (T) levels but differing in their gonadotrophin profiles.
- Closing excerpt
- 20 kg/m²; P ConclusionThis study demonstrated a significant difference in lean mass between Klinefelter and Kallmann syndromes, supporting a potential role for FSH in modulating muscle mass independently of T levels.
- Interpretation limits
- Verbatim excerpts from the authors’ abstract; the closing excerpt may describe a finding, limitation or recommendation. Design, population, effect size and uncertainty have not been independently extracted or appraised. Read the complete abstract and linked paper before interpreting the findings.
Read complete abstract (213 words)
ContextKlinefelter syndrome and Kallmann syndrome are 2 rare genetic disorders characterized by reduced testosterone (T) levels but differing in their gonadotrophin profiles. To date, no studies have directly compared body composition in these 2 syndromes.ObjectiveThis work aimed to assess the prevalence of altered body composition parameters in patients with Klinefelter and Kallmann syndromes and to compare body composition between the 2 groups. Secondary objectives included evaluating associations between body composition, bone mineral density (BMD), and serum follicle-stimulating hormone (FSH) levels.MethodsThis single-center, retrospective observational study included 50 patients, 29 with Klinefelter and 21 with Kallmann syndrome receiving T replacement therapy. Body composition was evaluated using whole-body dual-energy x-ray absorptiometry (DXA), which provided measurements of appendicular lean mass (ALM), total body fat (TBF), visceral adipose tissue (VAT), the ALM-to-height² ratio (appendicular lean mass index, ALMI), and the ALM-to-weight ratio.ResultsRadiologic sarcopenic obesity was identified in 7 patients (14%; 6/29 Klinefelter, 1/21 Kallmann), while osteosarcopenic obesity was found in 2 patients (4%), both with Klinefelter syndrome. Patients with Kallmann syndrome had significantly higher ALMI values than those with Klinefelter syndrome (8.37 ± 1.15 vs 7.28 ± 1.20 kg/m²; P ConclusionThis study demonstrated a significant difference in lean mass between Klinefelter and Kallmann syndromes, supporting a potential role for FSH in modulating muscle mass independently of T levels.
Abstract reproduced from the open-access article under the recorded cc by licence; © the authors. PMID 41073368 · DOI · PMC13016807
Key reviews and meta-analyses
The most cited review-type papers among PubMed’s best-match results for this heading, listed with bibliographic details only. Follow the links for the full text and access terms.
- Research article Klinefelter's syndrome [5]
- Research article Clinical review: Klinefelter syndrome--a clinical update [6]
- Research article Sperm recovery and ICSI outcomes in Klinefelter syndrome: a systematic review and meta-analysis [7]
- Research article Natural history of seminiferous tubule degeneration in Klinefelter syndrome [8]
- Research article Klinefelter syndrome [9]
- Research article Klinefelter syndrome and other sex chromosomal aneuploidies [10]
References
- Bonomi M, Rochira V, Pasquali D, Balercia G, Jannini EA, Ferlin A, et al.. Klinefelter syndrome (KS): genetics, clinical phenotype and hypogonadism. . 2017. PMID 27644703 · DOI · PMC5269463
- Skakkebæk A, Nielsen MM, Trolle C, Vang S, Hornshøj H, Hedegaard J, et al.. DNA hypermethylation and differential gene expression associated with Klinefelter syndrome. . 2018. PMID 30213969 · DOI · PMC6137224
- Bishop DV, Scerif G. Klinefelter syndrome as a window on the aetiology of language and communication impairments in children: the neuroligin-neurexin hypothesis. . 2011. PMID 21418292 · DOI · PMC3107947
- Buoso C, Delbarba A, Riva M, Artifoni G, Gatta E, Farina D, et al.. Body Composition by DXA in Patients with Klinefelter and Kallmann Syndrome: The Kama Study. . 2026. PMID 41073368 · DOI · PMC13016807
- Lanfranco F, Kamischke A, Zitzmann M, Nieschlag E. Klinefelter's syndrome. Lancet. 2004. PMID 15262106 · DOI
- Groth KA, Skakkebæk A, Høst C, Gravholt CH, Bojesen A. Clinical review: Klinefelter syndrome--a clinical update. J Clin Endocrinol Metab. 2013. PMID 23118429 · DOI
- Corona G, Pizzocaro A, Lanfranco F, Garolla A, Pelliccione F, Vignozzi L, et al.. Sperm recovery and ICSI outcomes in Klinefelter syndrome: a systematic review and meta-analysis. Hum Reprod Update. 2017. PMID 28379559 · DOI
- Aksglaede L, Wikström AM, Rajpert-De Meyts E, Dunkel L, Skakkebaek NE, Juul A. Natural history of seminiferous tubule degeneration in Klinefelter syndrome. Hum Reprod Update. 2006. PMID 16172111 · DOI
- Smyth CM, Bremner WJ. Klinefelter syndrome. Arch Intern Med. 1998. PMID 9645824 · DOI
- Visootsak J, Graham JM. Klinefelter syndrome and other sex chromosomal aneuploidies. Orphanet J Rare Dis. 2006. PMID 17062147 · DOI · PMC1634840
About this article
- Sources
- NLM Medical Subject Headings (definition, synonyms); NCBI PubMed (counts, identifiers); Europe PMC (open-access abstracts and citation counts).
- Verification
- Every reference was resolved against PubMed on 2026-10-31; title, year and DOI matched.
- Review state
- automated source verified; no human expert review has been recorded yet.
- Version
- 1, last updated 2026-10-29.
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Evidence strength
EvidenceHelix's computed view of the study designs behind this topic: how common meta-analyses, randomized trials and reviews are, how recent the literature is, and a plain-language reading. It describes the design mix of the literature. It is not a quality appraisal of any study, and it is not medical advice.