F1000Research 2019, 8(F1000 Faculty Rev):112 Last updated: 31 MAR 2022

REVIEW

Recent advances in managing and understanding Klinefelter

syndrome [version 1; peer review: 2 approved]
Priyanka Bearelly, Robert Oates
Urology, Boston University School of Medicine, 725 Albany Street, Suite 3B, Boston, MA, 02118, USA

v1 First published: 28 Jan 2019, 8(F1000 Faculty Rev):112 Open Peer Review
https://doi.org/10.12688/f1000research.16747.1
Latest published: 28 Jan 2019, 8(F1000 Faculty Rev):112
https://doi.org/10.12688/f1000research.16747.1 Approval Status

1 2
Abstract
Klinefelter syndrome can present as a wide spectrum of clinical version 1
manifestations at various stages in life, making it a chromosomal 28 Jan 2019

disorder with no standardized set of guidelines for appropriate

management. Understanding the genetic and hormonal causes of this Faculty Reviews are review articles written by the
syndrome can allow physicians to treat each patient on a more prestigious Members of Faculty Opinions. The
individualized basis. The timing of diagnosis and degree of symptoms
articles are commissioned and peer reviewed
can guide management. This report will provide an updated review of
the clinical presentation at various stages in life and the implications before publication to ensure that the final,
for management. published version is comprehensive and

Keywords accessible. The reviewers who approved the final

Klinefelter Syndrome, azoospermia, testis, TESE, 47, XXY version are listed with their names and
affiliations.

1. Richard N. Yu, Boston Children’s Hospital,

Boston, USA

2. Claus H. Gravholt , Aarhus University

Hospital, 8200, Aarhus, Denmark

Any comments on the article can be found at the

end of the article.

 
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Corresponding author: Robert Oates ([email protected])

Author roles: Bearelly P: Conceptualization, Writing – Original Draft Preparation, Writing – Review & Editing; Oates R:
Conceptualization, Supervision, Writing – Original Draft Preparation, Writing – Review & Editing
Competing interests: No competing interests were disclosed.
Grant information: The author(s) declared that no grants were involved in supporting this work.
Copyright: © 2019 Bearelly P and Oates R. This is an open access article distributed under the terms of the Creative Commons
Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
cited.
How to cite this article: Bearelly P and Oates R. Recent advances in managing and understanding Klinefelter syndrome [version 1;
peer review: 2 approved] F1000Research 2019, 8(F1000 Faculty Rev):112 https://doi.org/10.12688/f1000research.16747.1
First published: 28 Jan 2019, 8(F1000 Faculty Rev):112 https://doi.org/10.12688/f1000research.16747.1

 
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 F1000Research 2019, 8(F1000 Faculty Rev):112 Last updated: 31 MAR 2022

Introduction XY infants. Less than 3% to 10% of patients are diagnosed dur-

Klinefelter syndrome (KS) is a common male chromosomal dis- ing the prepubertal period4. Tall stature may be seen, but not
order (47, XXY) that has been a topic of intrigue and inquiry always, because of increased dosage of the sex chromosome-
since the 1940s, when it was first described1. It is a subject of related short stature homeobox-containing gene (SHOX), which
interest because of its wide spectrum of clinical manifestations, resides in the pseudoautosomal region of both X and Y and is
which include certain physical features, cognitive delays, and not subject to X-chromosomal inactivation8. Additional physical
azoospermia. features include cryptorchidism, gynecomastia, hypotonia, hyper-
telorism, clinodactyly, elbow dysplasia, pes planus, and a high
The chromosomal aberration found in KS is due to either arched palate9.
meiotic or mitotic non-disjunction, leading to sex-chromosomal
aneuploidy. Two genetic variations exist. The majority (90%) of These characteristics may be accompanied by learning difficulties
cases present as a pure form with a 47, XXY karyotype, whereas that may manifest as attention disorders and speech or language
the remaining 10% include the following sex-chromosomal impediments. Early literature has also suggested a higher preva-
abnormalities: mosaicism (46, XY/47, XXY), higher-grade aneu- lence of autism spectrum disorder, attention-deficit/hyperactiv-
ploidy (48, XXXY; 49, XXXXY), and structurally abnormal ity disorder, and schizophrenia; however, results are somewhat
X chromosomes2. incomplete, as those studies did not take into account family
history of mental illness or learning disabilities10. Though these
KS has been reported to occur in 1 out of 600 male births, features are more apparent in the severe chromosomal aneuploi-
approximately 64% of which remain undiagnosed throughout dies (that is, 49, XXXXY), KS males may exhibit “language-
life3,4. However, KS may be recognized during the prenatal, pre- based learning disabilities, decreased fine motor skills, and
pubertal, adolescent, or adult period. A patient’s management is discrepancies between nonverbal and verbal cognitive abilities”
guided by the extent and severity of clinical features as well as in the sense that visuoperceptual and nonverbal skills appear to be
timing of presentation. strengths11. In a cross-sectional study examining a prepuber-
tal KS cohort, the presenting characteristic that ultimately led
How does management differ according to time of to diagnosis was developmental delay (11.6%)12. Gropman and
diagnosis? Samango-Sprouse13 describe how young KS boys may have
There is no single, classic phenotype that can describe KS. The resultant academic difficulties in school, which broaches the
familiar description of tall stature with a thin, eunuchoid body topic of early diagnosis and whether testosterone replacement
habitus is not only inaccurate but also inadequate. There are no can prove advantageous. Although it is clear that androgens play
distinct dysmorphic features, and presentation may vary accord- a role in neurodevelopment, the progressive and more severe
ing to the degree of gonadal dysfunction5. The severity of the presentations of cognitive and motor delays seen with each
presentation is also strongly correlated with the severity of the additional X chromosome suggest a gene dosage effect of the
sex-chromosome aneuploidy (that is, higher-grade aneuploidies). X chromosome. In their double-blind randomized controlled trial,
A prepubertal boy may be diagnosed during the workup of cryp- Ross et al. showed that 2 years of low-dose androgen treatment
torchidism or mild developmental delay, whereas KS may be “did not have significant effects on most aspects of cognition
discovered initially in the older individual during an infertil- (general cognition, verbal skills, working memory)”14. Although
ity evaluation. Some physicians believe that delay in diagnosis the question of whether testosterone replacement would have
can increase the morbidity of the patient; therefore, it is impor- a positive impact remains, early intervention with educational
tant for practitioners to become familiar with this spectrum of supports such as tutoring and counseling may be beneficial.
features.
Diagnosis of the adolescent KS male can be more challenging.
There are no telltale physical signs of KS at birth. An increas- The degree of virilization is dependent upon the level of testicu-
ingly important means of diagnosis is through prenatal testing. lar testosterone production. The initial rise in testosterone levels
There is a growing utilization of non-invasive prenatal screen- during puberty may mirror that of a 46, XY male but typically
ing by cell-free fetal DNA testing. This test can identify the plateau at low to low normal values. Although external second-
presence of extra chromosomes—autosomal and sex6. How- ary sexual characteristics may appear Tanner stage-appropriate
ever, Nieschlag, Ferlin, Gravholt et al. provided a summary of as puberty progresses, reduced testicular volume is almost
the Second International Workshop on Klinefelter Syndrome universally present. The average testicular volume for a KS
(Münster, Germany, in 2016), and one of the topics addressed postpubertal male is 2 to 5 mL15. However, in a minority of
was the advisability of neonatal screening and diagnosis7. cases, the degree of hypogonadism can be so severe that there
Whereas Rogol argued that there are recognizable benefits to may be minimal or no signs of pubertal development, prompting
neonatal detection, Gravholt cautioned that there is yet no proof further workup. Testosterone supplementation to boost pubertal
that early detection necessarily results in a reduction in morbid- advancement may be of use in these cases.
ity and mortality with an improvement in outcomes when large
populations are screened. Therefore, even expert opinion diverges KS discovered in adulthood is often under the circumstances
on this issue at this time. The mini-puberty, namely activated of evaluation for primary infertility. Although 8% of the KS
luteinizing hormone (LH) and follicle-stimulating hormone population may have detectable sperm in the ejaculate, the major-
(FSH) release in the first few months of life, matches that of 46, ity will have non-obstructive azoospermia16. Typically, LH and

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FSH will be elevated, testosterone will be low normal, and semen aged 14 to 19, GCTs are almost exclusively mediastinal. The
volume will be adequate. Erectile function is not commonly exact biological etiology driving mediastinal GCT development
impacted. is unknown at this point. These tumors may present at a young
age as precocious puberty because of human chorionic gona-
What comorbidities can accompany Klinefelter dotropin secretion by the tumor cells. Older boys may present
syndrome? with chest pain or respiratory symptoms due to tumor location.
As reviewed by Kanakis and Nieschlag17 and Gravholt et al.18, Although today’s literature describes primarily pediatric cases
cardiovascular, cerebrovascular, and metabolic syndrome and of mediastinal GCTs in KS, adult males with KS have also been
other comorbidities are increased in patients with KS. Cardio- shown to develop these masses29. Males with mediastinal GCTs
vascular mortality is higher in this population and this is usually should be screened for KS.
due to aortic valve anomalies, pulmonary embolism, peripheral
vascular disease, and deep vein thrombosis19. For example, as In her literature review of the data to date, Brinton concluded
Zöller et al. detailed in their Swedish cohort study, the cumula- that the risk of breast cancer in the male with KS is 20- to 30-
tive incidences of venous thromboembolism in men with KS were fold higher than expected and that there is a 60-fold increase in
8.6% at 50 years of age and 20.8% at 70 years of age20. In efforts mortality30. With the absolute incidence still being quite low, rou-
to explain this association, Valasek et al.21 reported on a pediat- tine screening mammography is not a formal recommendation30.
ric case in which the boy also had a type 1 protein C deficiency
whereas Erkal et al.22 did not find a difference in PAI-1 gene What is the impact on spermatogenesis and
polymorphisms when comparing KS patients and cohorts. Finally, implications for fertility?
Glueck et al. caution that perhaps prothrombotic long-term KS is found to be the etiology of infertility in 10% of azoosper-
testosterone replacement therapy (TRT) in conjunction with mic males and accounts for up to 2% of infertility in the
undiagnosed familial thrombophilia may be the combination that general male population31. To give a brief embryologic
leads to thromboembolism in the patient with KS23. They advo- overview, germ cells migrate to the genital ridges and populate the
cate for thrombophilia screening prior to initiation of TRT23. nascent seminiferous tubules. The Sertoli cells and Leydig cells
Cardiac structural abnormalities include left ventricular diastolic form within and around the seminiferous tubules, respectively.
dysfunction, mitral valve prolapse, and increased thickness of Beginning just after birth, peaking in the 4th to 10th week after
inner tunica of carotid arteries24. Decreased exercise tolerance delivery and nadiring to prepubertal levels by 6 months of age,
is also common. It is reasonable for practitioners to consider a there is a surge in pituitary gonadotropins, also known as “mini
diagnostic echocardiogram. puberty”, which stimulates the expansion and limited differen-
tiation of the spermatogonial stem cell pool32. The seminiferous
Cerebrovascular mortality may be secondary to subarachnoid tubules lengthen, testis volume enlarges, and Sertoli cell
hemorrhage, rupture of an intracranial saccular aneurysm, or number increases33. Cell cycle activity in the testes remains
a thrombotic event25. The KS population is also noted to have a fairly quiescent until the initiation of puberty as a result of
higher prevalence of metabolic syndrome and dyslipidemia. hypothalamic gonadotropin-releasing hormone (GnRH) stimu-
In one cross-sectional study, 47% of subjects with KS were lation of pituitary LH and FSH production and release. LH trig-
noted to have metabolic syndrome, including increased total gers intratesticular testosterone manufacture while FSH sparks
body fat, waist circumference, insulin resistance, triglycerides, Sertoli cell maturation and spermatogenic induction. In the
and low-density lipoproteins26. KS male specifically, peripheral serum testosterone values rise
but typically level off in the low normal range while the vast
Men with KS may have reduced bone mineral density in the majority of 47, XXY spermatogonia become apoptotic as they
lumbar spine, femoral neck, and total hip, but TRT does not amel- fail to complete meiosis.
iorate all of these findings27. As Tahani et al. state, “bone loss
in KS might, at least in part, be independent of hypogonadism”27. Classic puberty in the adolescent heralds the start of intrates-
ticular testosterone production, necessary for spermatogenesis.
Is there a predisposition to malignancy? Although testosterone levels do increase on schedule, males with
Although the overall incidence of malignancy is not higher KS experience a blunting of both Sertoli and Leydig cell func-
in the KS population, there is an increase in multiple types of tion after the initiation of puberty. There is progressive apoptosis
cancer, including breast cancer and extragonadal germ cell tumors of the 47, XXY spermatogonia, ultimately resulting in azoosper-
(GCTs). However, the overall incidence is so low that routine mia in adulthood34. However, it cannot be simply that an inability
screening of an asymptomatic KS male is not recommended. to sequence through the meiotic cascade leads invariably to such
rapid and dramatic cell senescence and demise, as we would then
According to Williams et al., 3% of GCTs diagnosed in males expect the same events to unfold in spermatocytic maturation arrest
under the age of 19 occur in boys with a 47, XXY karyotype28. resulting from genetic causes. In this latter anomaly of sperma-
Conversely, the risk of developing a GCT in KS patients of this age togenesis, viable spermatogonia and spermatocytes stack up like
group is 1 in 4,000 (risk ratio of 18.8) compared with the normal cars on a highway behind an impenetrable roadblock—remaining
46, XY male population. In their study, the parent of origin of the alive but prevented from progressing further. However, the pres-
supernumerary X chromosome was split equally between mother ence of spermatozoa in about 50% of KS testes is best explained
and father. Most GCTs in males with KS are mediastinal in loca- by postulating a low level of gonosomal mosaicism. Escap-
tion and teratomatous in histology. In fact, among KS males ing death and proceeding through meiosis I and II, as well as

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spermiogenesis, are scattered 46, XY spermatogonia which, ongoing spermatogenesis in 20 biopsies from peripubertal boys,
through a second quirk of nature, have lost the additional X chro- and sperm detection in only 1 out of 20 adolescent boys under-
mosome, resorted to a normal diploid state, and come to reside going TESE. However, in the older adult patients with KS, TESE
in a seminiferous tubule here or a seminiferous tubule there. The recovered fully formed spermatozoa in 48% with no difference
distribution is most likely random, explaining the patternless and noted between the various age groups (18–25, 26–30, 31–35,
haphazard location within the tiny testes of spermatogenically and >35 years), a finding supported by the meta-analysis by
healthy tubules. Corona et al.35. To summarize, van Saen et al. concluded that
“sperm recovery by TESE at early adolescent age does not
Until the advent of assisted reproductive techniques, males appear to result in higher sperm retrieval efficiency compared to
with KS were considered to be sterile. However, with further TESE at adult age”. Rives et al. also cautioned that “no predic-
understanding that these men may have focal areas of sperma- tive factors can actually demonstrate that early diagnosis of KS
togenesis within the testes, testicular sperm extraction (TESE) would allow increasing the chance of sperm retrieval”44. Taking a
has become a mainstay treatment option for sperm harvesting slightly different and novel focus, Ragab et al. recently reported on
and future reproduction35–37. the microsurgical TESE (mTESE) SSR in two overall groups
of patients with KS: 31% in those with a history of unilateral or
As described in the preceding paragraph, during mitotic renewal bilateral cryptorchidism and 38% in those with eutopic testes
or differentiation of an occasional 47, XXY spermatogonial stem at birth—no statistical difference was seen. SSRs also did not
cell, the extra X chromosome may be lost because of anaphase differ between those KS men born with unilateral or bilateral
lag38. Subsequently, the resultant 46, XY daughter cells have the undescended testes45. Embedded within the excellent data
genetic opportunity to replicate. The extent of spermatogenesis of their study is the fact that, in the group of KS males with
in a male with KS appears then to depend on the presence eutopic testes, the median age at which mTESE found sperm
and quantity of these 46, XY germ cells. Some argue that TESE was comparable to the age at which no sperm were retrieved: 23
procedures for sperm cryopreservation should be pursued (range 15–26) and 20.5 (range 17–48), respectively45.
during the adolescent period, or possibly earlier, prior to the pro-
gression of spermatogonial apoptosis. The opposite school of In a discussion of preferred surgical techniques, a large system-
thought believes that TESE should be delayed until adulthood. atic review by Corona et al., which compares techniques of TESE
As reviewed recently by Oates, many studies have examined this in patients with KS specifically, demonstrates similar sperm
relationship between age at time of TESE and rate of successful retrieval rates with both conventional TESE and mTESE35. How-
surgical sperm retrieval (SSR)39. Although some of the evidence ever, studies looking more generally at men with non-obstructive
is contradictory, the majority have found no difference in azoospermia do suggest that there is an increased sperm
TESE outcomes among different age groups39,40. In fact, Franik retrieval rate in mTESE46. With regard to the ultimate goal of
et al. demonstrated that SSR was lower in patients below the age reproduction, the couple must proceed with intracytoplasmic
of 16 who underwent TESE41. sperm injection (ICSI) to use the spermatozoa that may be retrieved
in either the freshly harvested or the frozen-thawed state. Recent
To elaborate on and investigate spermatogenic potential in studies report an average sperm retrieval rate per TESE pro-
47, XXY testes, van Saen et al. found that only 30% of peripu- cedure of 34% to 44% and an average live birth rate per ICSI
bertal patients from 12 to 16 years had any germ cells on cycle of 29% to 43%31,35. In their latest report, aptly titled “Is
testicular biopsy, suggesting that germ cell loss begins well before genetic fatherhood within reach for all azoospermic Klinefelter
puberty40. The authors’ study beautifully addressed the timing men?”, Vloeberghs et al. caution that a multiplicity of factors
of germ cell loss and the rate of TESE success in a number of conspire to actually determine the ultimate chance of biological
different age ranges. They examined the testes of five fetuses with fatherhood, not just the probability of finding sperm on TESE
a 47, XXY karyotype and concluded that the number of germ or mTESE31. To wit, only 14 out of 138 (10.1%) KS men
cells identified “was not significantly different from controls”. and their partners starting treatment succeeded in having a
There was very little fibrosis noted. However, Winge et al. observed live birth. Hormonal parameters have not yet been shown to
that, in eight KS fetuses they studied, germ cell loss may already predict the success of TESE31.
be occurring, specifically failure of gonocytes to differentiate
into the slightly more advanced stage of pre-spermatogonia42. Sex-chromosome aneuploidies are also fascinating from a purely
The authors suggested an upregulation of X-chromosomal genomic perspective. Although the supernumerary X chromo-
transcripts and enrichment of certain long non-coding RNAs some undergoes inactivation, there are clearly genes that escape
(ncRNAs) as a possible etiologic explanation. Winge et al., in a inactivation that are either directly or indirectly responsible for
further study, concluded that the mechanisms underlying germ cell the KS phenotype. Via RNA sequencing (RNA-seq), Winge
loss may be different in the fetal, prepubertal, and adult et al. demonstrated “211 differentially expressed transcripts in
stages and that aberrant maturation of Sertoli and Leydig cells the fetal KS testis”, a significant enrichment of X-chromosomal
may also be contributory43. transcripts and long ncRNAs42. This suggested to them that the
failure of gonocyte differentiation into pre-spermatogonia in the
In their study mentioned above, van Saen et al. also documented fetal testis led directly to the extremely poor (or absent) sper-
a paucity of detectable germ cells in prepubertal patients, no matogenesis in the adult KS testis. In their “companion” study

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on adult KS testes, they conclude that disturbed maturation of component of management with regard to pubertal advances, it
Sertoli and Leydig cells may further inhibit, and directly impair, will not have any positive effects on spermatogenesis or fertil-
spermatogenesis as well43. ity. However, some studies suggest that TRT does not appear to
impact sperm retrieval rates in patients with KS53,54. Some prac-
In their beautiful 2018 report, Skakkebæk et al. further defined the titioners may employ replacement therapy just after the onset of
genetic underpinnings of the phenotypic findings in Klinefelter puberty, typically in the form of gel, as compliance is higher54.
males47. That is, they asked how the additional X chromo- Aromatase inhibitors may be used in males with gynecomastia.
some is influencing form and function. They performed both
genome-wide DNA methylation and genome-wide RNA-seq Conclusions
of peripheral blood leukocytes in 67 and 9 patients with KS, As a genetic condition that affects 1 in 600 live male births, KS
respectively. They had similar numbers of 46, XY male and is being seen commonly enough that it is important for prac-
46, XX female controls for both groups. They built on previous titioners to understand the wide spectrum of issues and the
work linking changes in the methylome and transcriptome of multidisciplinary approach that is required to appropriately treat
what we see in KS males48,49. They found 11 differentially meth- these patients. It is also essential to take note of distinct features
ylated positions (DMPs) on the two X chromosomes when that are known to be associated with KS, as this allows providers
comparing KS and female controls (corresponding to eight the opportunity to recognize undiagnosed cases. Along these
genes) and 168 autosomal DMPs between KS and control males lines, there is increasing momentum in genomic studies that
(corresponding to 85 genes). In their RNA-seq expression are beginning to shed light on the differential gene expression
profiling studies, they found 31 differentially expressed genes that may explain the KS phenotypes and the variability within.
between KS and male controls. Perhaps most importantly was the
discovery that there were 23 differentially expressed autosomal Despite ongoing investigations, there are still many essential
and seven differentially expressed X-chromosomal ncRNA genes questions, including whether hormone replacement therapy
between the KS and control males. ncRNA genes may be involved plays a beneficial role and what timing is appropriate for sperm
in X inactivation as well as neurodevelopment and cognition50,51. retrieval for those interested in reproduction. The evidence to
Their conclusion forecasts future research and exploration efforts date suggests that hormone replacement therapy with testoster-
to causally link exact gene expression/regulation of the altered one may be valuable for peripubertal KS boys who appear to
phenotype of KS males: “in conclusion, our results demon- have delayed initiation of puberty and distinctly lack viriliza-
strate a unique epigenetic and genetic landscape in KS involv- tion. There is also a lack of data to support the advantage of
ing both the X chromosome and the autosomal chromosomes, TESE in the adolescent compared with the adult patient with
with few correlations between methylation values and gene KS. In fact, the counterargument, that optimal timing for TESE
expression”47. Raznahan et al. added to this growing body of data in the patient with KS is during early adulthood, is becoming
by also reporting on sex-chromosome dosage effects on gene more apparent.
expression in hopes of teasing out why 47, XXY; 47, XXX; 47,
XYY; 45, XO; and 48, XXYY are all phenotypically distinct52.

A fair amount of focus has been placed on the role of androgen Grant information
replacement therapy in KS, as testosterone levels are known The author(s) declared that no grants were involved in supporting
to be low or low normal. Although this may be an important this work.

References F1000 recommended

1. KLINEFELTER HF, REIFENSTEIN EC, ALBRIGHT F: Syndrome Characterized by

7. Nieschlag E, Ferlin A, Gravholt CH, et al.: The Klinefelter syndrome: current
Gynecomastia, Aspermatogenesis without A-Leydigism, and Increased Excretion
management and research challenges. Andrology. 2016; 4(3): 545–9.
of Follicle-Stimulating Hormone. J Clin Endocrinol Metab. 1942; 2(11): 615–27.
PubMed Abstract | Publisher Full Text | F1000 Recommendation
Publisher Full Text
2. Rajender A, Oates RD: Evaluation and Management of Klinefelter Syndrome. 8. Ottesen AM, Aksglaede L, Garn I, et al.: Increased Number of Sex Chromosomes
AUA Updat Ser. 2018; 37. Affects Height in a Nonlinear Fashion: A Study of 305 Patients With Sex
Reference Source Chromosome Aneuploidy. Am J Med Genet. 2017; 55(33): 9557–9561.
3. Bojesen A, Juul S, Gravholt CH: Prenatal and postnatal prevalence of Klinefelter 9. Akcan N, Poyrazoğlu Ş, Baş F, et al.: Klinefelter Syndrome in Childhood:
syndrome: a national registry study. J Clin Endocrinol Metab. 2003; 88(2): 622–6. Variability in Clinical and Molecular Findings. J Clin Res Pediatr Endocrinol.
PubMed Abstract | Publisher Full Text 2018; 10(2): 100–7.
4. Abramsky L, Chapple J: 47,XXY (Klinefelter syndrome) and 47,XYY: estimated PubMed Abstract | Publisher Full Text | Free Full Text | F1000 Recommendation
rates of and indication for postnatal diagnosis with implications for prenatal 10. Bruining H, Swaab H, Kas M, et al.: Psychiatric characteristics in a self-selected
counselling. Prenat Diagn. 1997; 17(4): 363–368. sample of boys with Klinefelter syndrome. Pediatrics. 2009; 123(5): e865–e870.
PubMed Abstract | Publisher Full Text PubMed Abstract | Publisher Full Text
5. Bourke E, Herlihy A, Snow P, et al.: Klinefelter syndrome - a general practice 11. Leggett V, Jacobs P, Nation K, et al.: Neurocognitive outcomes of individuals
perspective. Aust Fam Physician. 2014; 43(1): 38–41. with a sex chromosome trisomy: XXX, XYY, or XXY: a systematic review. Dev
PubMed Abstract Med Child Neurol. 2010; 52(2): 119–29.
6. Samango-Sprouse C, Keen C, Sadeghin T, et al.: The benefits and limitations PubMed Abstract | Publisher Full Text | Free Full Text
of cell-free DNA screening for 47, XXY (Klinefelter syndrome). Prenat Diagn. 12. Close S, Fennoy I, Smaldone A, et al.: Phenotype and Adverse Quality of Life in
2017; 37(5): 497–501. Boys with Klinefelter Syndrome. J Pediatr. 2015; 167(3): 650–7.
PubMed Abstract | Publisher Full Text | F1000 Recommendation PubMed Abstract | Publisher Full Text

Page 6 of 8
 F1000Research 2019, 8(F1000 Faculty Rev):112 Last updated: 31 MAR 2022

13. Gropman A, Samango-Sprouse CA: Neurocognitive variance and neurological 843–65.

underpinnings of the X and Y chromosomal variations. Am J Med Genet C PubMed Abstract | Publisher Full Text | Free Full Text | F1000 Recommendation
Semin Med Genet. 2013; 163C(1): 35–43.
PubMed Abstract | Publisher Full Text 35. Corona G, Pizzocaro A, Lanfranco F, et al.: Sperm recovery and ICSI
outcomes in Klinefelter syndrome: a systematic review and meta-analysis.
14. Ross JL, Kushner H, Kowal K, et al.: Androgen Treatment Effects on Motor Hum Reprod Update. 2017; 23(3): 265–75.
Function, Cognition, and Behavior in Boys with Klinefelter Syndrome. J Pediatr. PubMed Abstract | Publisher Full Text | F1000 Recommendation
2017; 185: 193–199.e4. 36. Palermo GD, Schlegel PN, Sills ES, et al.: Births after intracytoplasmic injection
PubMed Abstract | Publisher Full Text | F1000 Recommendation of sperm obtained by testicular extraction from men with nonmosaic
15. Rocher L, Moya L, Correas JM, et al.: Testis ultrasound in Klinefelter Klinefelter’s syndrome. N Engl J Med. 1998; 338(9): 588–90.
syndrome infertile men: making the diagnosis and avoiding inappropriate PubMed Abstract | Publisher Full Text
management. Abdom Radiol (NY). 2016; 41(8): 1596–603. 37. Tournaye H, Staessen C, Liebaers I, et al.: Testicular sperm recovery in nine
PubMed Abstract | Publisher Full Text | F1000 Recommendation 47,XXY Klinefelter patients. Hum Reprod. 1996; 11(8): 1644–9.
16. Hotaling J, Carrell DT: Clinical genetic testing for male factor infertility: current PubMed Abstract | Publisher Full Text
applications and future directions. Andrology. 2014; 2(3): 339–50. 38. Bonomi M, Rochira V, Pasquali D, et al.: Klinefelter syndrome (KS): genetics,
PubMed Abstract | Publisher Full Text clinical phenotype and hypogonadism. J Endocrinol Invest. 2017; 40(2): 123–34.
17. Kanakis GA, Nieschlag E: Klinefelter syndrome: more than hypogonadism. PubMed Abstract | Publisher Full Text | Free Full Text | F1000 Recommendation
Metabolism. 2018; 86: 135–44. 39. Oates R: Adolescent Klinefelter syndrome: is there an advantage to testis
PubMed Abstract | Publisher Full Text | F1000 Recommendation tissue harvesting or not? [version 1; referees: 3 approved] F1000Res. 2016; 5:
pii: F1000 Faculty Rev-1595.
18. Gravholt CH, Chang S, Wallentin M, et al.: Klinefelter Syndrome: Integrating PubMed Abstract | Publisher Full Text | Free Full Text
Genetics, Neuropsychology, and Endocrinology. Endocr Rev. 2018; 39(4): 389–423.
PubMed Abstract | Publisher Full Text | F1000 Recommendation 40. Van Saen D, Vloeberghs V, Gies I, et al.: When does germ cell loss and
19. Swerdlow AJ, Higgins CD, Schoemaker MJ, et al.: Mortality in patients with fibrosis occur in patients with Klinefelter syndrome? Hum Reprod. 2018; 33(6):
Klinefelter syndrome in Britain: a cohort study. J Clin Endocrinol Metab. 2005; 1009–22.
90(12): 6516–22. PubMed Abstract | Publisher Full Text | F1000 Recommendation
PubMed Abstract | Publisher Full Text 41. Franik S, Hoeijmakers Y, D'Hauwers K, et al.: Klinefelter syndrome and
20. Zöller B, Ji J, Sundquist J, et al.: High Risk of Venous Thromboembolism in fertility: sperm preservation should not be offered to children with Klinefelter
Klinefelter Syndrome. J Am Heart Assoc. 2016; 5(5): pii: e003567. syndrome. Hum Reprod. 2016; 31(9): 1952–9.
PubMed Abstract | Publisher Full Text | Free Full Text | F1000 Recommendation PubMed Abstract | Publisher Full Text | F1000 Recommendation
21. Valasek AE, Warren P, Kumar R: Klinefelter syndrome as a risk factor for 42. Winge SB, Dalgaard MD, Jensen JM, et al.: Transcriptome profiling of fetal
recurrent deep vein thrombosis in an adolescent male: Significance of a Klinefelter testis tissue reveals a possible involvement of long non-coding
thorough physical examination. Pediatr Blood Cancer. 2018; 65(8): e27080. RNAs in gonocyte maturation. Hum Mol Genet. 2018; 27(3): 430–9.
PubMed Abstract | Publisher Full Text PubMed Abstract | Publisher Full Text | F1000 Recommendation
22. Erkal B, Kalayci Yigin A, Palanduz S, et al.: The Effect of PAI-1 Gene Variants 43. Winge SB, Dalgaard MD, Belling KG, et al.: Transcriptome analysis of
and PAI-1 Plasma Levels on Development of Thrombophilia in Patients With the adult human Klinefelter testis and cellularity-matched controls reveals
Klinefelter Syndrome. Am J Mens Health. 2018; 12(6): 2152–6. disturbed differentiation of Sertoli- and Leydig cells. Cell Death Dis. 2018; 9(6):
PubMed Abstract | Publisher Full Text | Free Full Text 586.
23. Glueck CJ, Jetty V, Goldenberg N, et al.: Thrombophilia in Klinefelter PubMed Abstract | Publisher Full Text | Free Full Text | F1000 Recommendation
Syndrome With Deep Venous Thrombosis, Pulmonary Embolism, and 44. Rives N, Rives A, Rondanino C, et al.: Fertility Preservation in Klinefelter
Mesenteric Artery Thrombosis on Testosterone Therapy: A Pilot Study. Clin Syndrome Patients during the Transition Period. Endocr Dev. 2018; 33: 149–57.
Appl Thromb Hemost. 2017; 23(8): 973–9. PubMed Abstract | Publisher Full Text
PubMed Abstract | Publisher Full Text | F1000 Recommendation
45. Ragab MW, Cremers JF, Zitzmann M, et al.: A history of undescended testes
24. Pasquali D, Arcopinto M, Renzullo A, et al.: Cardiovascular abnormalities in in young men with Klinefelter syndrome does not reduce the chances for
Klinefelter syndrome. Int J Cardiol. 2013; 168(2): 754–9. successful microsurgical testicular sperm extraction. Andrology. 2018; 6(4):
PubMed Abstract | Publisher Full Text 525–31.
25. Salzano A, Arcopinto M, Marra AM, et al.: Klinefelter syndrome, PubMed Abstract | Publisher Full Text | F1000 Recommendation
cardiovascular system, and thromboembolic disease: review of literature and 46. Bernie AM, Mata DA, Ramasamy R, et al.: Comparison of microdissection
clinical perspectives. Eur J Endocrinol. 2016; 175(1): R27–R40. testicular sperm extraction, conventional testicular sperm extraction, and
PubMed Abstract | Publisher Full Text | F1000 Recommendation testicular sperm aspiration for nonobstructive azoospermia: a systematic
26. Bojesen A, Kristensen K, Birkebaek NH, et al.: The metabolic syndrome is review and meta-analysis. Fertil Steril. 2015; 104(5): 1099–103.e1-3.
frequent in Klinefelter’s syndrome and is associated with abdominal obesity PubMed Abstract | Publisher Full Text | F1000 Recommendation
and hypogonadism. Diabetes Care. 2006; 29(7): 1591–8.
PubMed Abstract | Publisher Full Text 47. Skakkebæk A, Nielsen MM, Trolle C, et al.: DNA hypermethylation and
differential gene expression associated with Klinefelter syndrome. Sci Rep.
27. Tahani N, Nieddu L, Prossomariti G, et al.: Long-term effect of testosterone 2018; 8(1): 13740.
replacement therapy on bone in hypogonadal men with Klinefelter Syndrome. PubMed Abstract | Publisher Full Text | Free Full Text | F1000 Recommendation
Endocrine. 2018; 61(2): 327–35. 48. Wan ES, Qiu W, Morrow J, et al.: Genome-wide site-specific differential
PubMed Abstract | Publisher Full Text | F1000 Recommendation methylation in the blood of individuals with Klinefelter syndrome. Mol Reprod
Dev. 2015; 82(5): 377–86.
28. Williams LA, Pankratz N, Lane J, et al.: Klinefelter syndrome in males with
PubMed Abstract | Publisher Full Text | Free Full Text
germ cell tumors: A report from the Children’s Oncology Group. Cancer. 2018;
124(19): 3900–8. 49. Belling K, Russo F, Jensen AB, et al.: Klinefelter syndrome comorbidities
PubMed Abstract | Publisher Full Text | Free Full Text | F1000 Recommendation linked to increased X chromosome gene dosage and altered protein
29. Pradhan D, Kaman L, Dhillon J, et al.: Mediastinal mixed germ cell tumor in an interactome activity. Hum Mol Genet. 2017; 26(7): 1219–29.
infertile male with Klinefelter syndrome:A case report and literature review. PubMed Abstract | Publisher Full Text | Free Full Text | F1000 Recommendation
J Cancer Res Ther. 2015; 11(4): 1034. 50. Salta E, De Strooper B: Noncoding RNAs in neurodegeneration. Nat Rev
PubMed Abstract | Publisher Full Text Neurosci. 2017; 18(10): 627–40.
30. Brinton LA: Breast cancer risk among patients with Klinefelter syndrome. Acta PubMed Abstract | Publisher Full Text
Paediatr. 2011; 100(6): 814–8. 51. Lee JT, Bartolomei MS: X-inactivation, imprinting, and long noncoding RNAs in
PubMed Abstract | Publisher Full Text | Free Full Text health and disease. Cell. 2013; 152(6): 1308–23.
PubMed Abstract | Publisher Full Text
31. Vloeberghs V, Verheyen G, Santos-Ribeiro S, et al.: Is genetic fatherhood
within reach for all azoospermic Klinefelter men? PLoS One. 2018; 13(7): 52. Raznahan A, Parikshak NN, Chandran V, et al.: Sex-chromosome dosage
e0200300. effects on gene expression in humans. Proc Natl Acad Sci U S A. 2018; 115(28):
PubMed Abstract | Publisher Full Text | Free Full Text | F1000 Recommendation 7398–403.
32. Kurtoğlu S, Baştuğ O: Mini puberty and its interpretation. Turk Pediatri Ars. 2014; PubMed Abstract | Publisher Full Text | Free Full Text | F1000 Recommendation
49(3): 186–91. 53. Plotton I, Giscard d'Estaing S, Cuzin B, et al.: Preliminary results of a
PubMed Abstract | Publisher Full Text | Free Full Text prospective study of testicular sperm extraction in young versus adult
33. Sharpe R, McKinnell C, Kivlin C, et al.: Proliferation and functional maturation of patients with nonmosaic 47,XXY Klinefelter syndrome. J Clin Endocrinol Metab.
Sertoli cells, and their relevance to disorders of testis function in adulthood. 2015; 100(3): 961–7.
Reproduction. 2003; 125(6): 769–84. PubMed Abstract | Publisher Full Text | F1000 Recommendation
PubMed Abstract
54. Mehta A, Paduch DA: Klinefelter syndrome: an argument for early
34. Davis SM, Rogol AD, Ross JL: Testis Development and Fertility Potential in aggressive hormonal and fertility management. Fertil Steril. 2012; 98(2): 274–83.
Boys with Klinefelter Syndrome. Endocrinol Metab Clin North Am. 2015; 44(4): PubMed Abstract | Publisher Full Text | F1000 Recommendation

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 F1000Research 2019, 8(F1000 Faculty Rev):112 Last updated: 31 MAR 2022

Open Peer Review

Current Peer Review Status:

Editorial Note on the Review Process

Faculty Reviews are review articles written by the prestigious Members of Faculty Opinions. The articles
are commissioned and peer reviewed before publication to ensure that the final, published version is
comprehensive and accessible. The reviewers who approved the final version are listed with their names
and affiliations.

The reviewers who approved this article are:

Version 1
1. Claus H. Gravholt
Department of Endocrinology and Department of Molecular Medicine, Aarhus University Hospital,
8200, Aarhus, Denmark
Competing Interests: No competing interests were disclosed.
2. Richard N. Yu
Department of Urology, Boston Children’s Hospital, Boston, MA, USA
Competing Interests: No competing interests were disclosed.

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