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The vicious circle of hypogonadism – abdominal obesity – insulin resistance in Klinefelter syndrome, with secondary consequences. Solid arrows indicates promotion, broken arrows indicates inhibition. VO2max is a measure of maximal oxygen consumption, a measure of physical fitness. This figure is reproduced from Bojesen et al.7 with permission.
Source publication
Klinefelter syndrome (KS) (47, XXY) is the most abundant sex-chromosome disorder, and is a common cause of infertility and hypogonadism in men. Most men with KS go through life without knowing the diagnosis, as only 25% are diagnosed and only a few of these before puberty. Apart from hypogonadism and azoospermia, most men with KS suffer from some d...
Context in source publication
Context 1
... the biological active high molecular weight subform of adiponectin was nonsuppressed. 86 Although speculative, it seems possible that hypogonadism in KS contributes to development of the metabolic syndrome and increases numerous cardiac risk factors, but also protects against ischemic heart disease by increasing levels of adiponectin in concert with nonelevated blood pressure (Figure 1). This hypothesis is supported by the finding of decreased mortality risk from ischemic heart disease in KS patients, 10 but findings from recent epidemiological studies in non-KS are contradictory and have demonstrated higher cardiovascular disease risk in men both in untreated hypogonadal men as well as in hypogonadal men after testosterone treatment. ...Similar publications
Bruton's agammaglobulinemia is a rare X-linked humoral immunodeficiency manifesting with recurrent bacterial infections early in life. Klinefelter's syndrome caused by an additional X chromosome is the most common sex chromosome disorder. A previously unreported association of these two conditions is described here.
In humans, the most common sex chromosomal disorder is Klinefelter syndrome (KS), caused by the presence of one or more extra X-chromosomes. KS patients display a varying adult phenotype but usually present with azoospermia due to testicular degeneration, which accelerates at puberty. The timing of the germ cell loss and whether it is caused by dys...
Citations
... KS is the most common hereditary cause of male hypogonadism and androgen deficiency, which are the sex chromosome abnormalities associated with male infertility. Attention must be paid to the following: Long-term male hypogonadism comprises a significant health risk, such as IGT, obesity, loss of muscle and bone mass, and MetS, introducing a vicious circle and further worsening the hypogonadism [17]. These complications can lead to type 2 diabetes, high blood pressure and cardiovascular disease, which can also lead to a markedly decreased quality of life [18,19]. ...
Background
Klinefelter Syndrome (KS) is a sex chromosomal syndrome usually with an extra X chromosome (47, XXY) in males, which has various phenotype (mosaicism 47, XXY/46, XY, or more chromosomes 48, XXXY, 49, XXXXY) and clinical features, including eunuchoid body proportions, abnormally long legs and arm span, gynecomastia, ynecomastia, absent or decreased facial and pubic hair, small hyalinized testes, small penis, below-normal verbal intelligence quotient, and learning difficulties. At present, there are no studies on the correlation between the clinical characteristics of patients with KS and the ultrastructural changes of intracellular organelles in testicular tissue in China.
Case presentation
Here we report the ultrastructure manifestation of the testis tissues in a KS patient with hypogonadism and androgen deficiency, to find a relationship between ultrastructural changes of organelles and spermatogenic dysfunction, clinical features, timing of surgery and metabolic abnormalities. It has been shown that the spermatocytes are absent and the ultrastructure of Sertoli cells and Leydig cells is obviously abnormal, which may lead to spermatogenic dysfunction, androgen deficiency, impaired glucose tolerance (IGT), and abdominal fat accumulation.
Conclusions
Based on the European Academy of Andrology (EAA) Gudilines on Klinefelter Syndrome, this study conducted a retrospective study on the diagnosis and treatment of one adult patient with KS, aiming to provide a standardized diagnosis and treatment for patients with KS. This study is also highly concerned with the correlation between the ultrastructural changes of target organs and clinical symptoms.
... Gains in X-vs. Y-chromosome dosages are also known to differentially impact testicular function in males-for example, progressive hypogonadism is seen in XXY/KS but not XYY [69]. It is therefore theoretically possible that some of the distinguishing behavioral features in XXY/KS as compared to XYY (e.g. ...
Do different genetic disorders impart different psychiatric risk profiles? This question has major implications for biological and translational aspects of psychiatry, but has been difficult to tackle given limited access to shared batteries of fine-grained clinical data across genetic disorders. Using a new suite of generalizable analytic approaches, we examine gold-standard diagnostic ratings, scores on 66 dimensional measures of psychopathology, and measures of cognition and functioning in two different sex chromosome aneuploidies (SCAs) - Klinefelter (XXY/KS) and XYY syndrome (n=102 and 64 vs. n=74 and 60 matched XY controls, total n=300). We focus on SCAs for their high collective prevalence, informativeness regarding differential X- vs. Y-chromosome effects, and potential relevance for normative sex differences. We show that XXY/KS elevates rates for most psychiatric diagnoses as previously reported for XYY, but disproportionately so for anxiety disorders. Fine-mapping across all 66 traits provides a detailed profile of psychopathology in XXY/KS which is strongly correlated with that of XYY (r=.75 across traits) and robust to ascertainment biases, but reveals: (i) a greater penetrance of XYY than KS/XXY for most traits except mood/anxiety problems, and (ii) a disproportionate impact of XYY vs. XXY/KS on social problems. XXY/KS and XXY showed a similar coupling of psychopathology with adaptive function and caregiver strain, but not IQ. This work provides new tools for deep-phenotypic comparisons of genetic disorders in psychiatry and uses these to detail unique and shared effects of the X- and Y-chromosome on human behavior.
... Small, hard testes are seen in all cases, and are caused by progressive tubulohyalinization and interstitial testicular fibrosis [1,3,4,16,30,39]. Hypogonadism also causes sexual dysfunction (decreased libido and erectile dysfunction) [3,4,47]. ...
... About 80-90% of KS cases present a non-mosaic karyotype (47,XXY), while the remaining 10-20% evidence a mosaic karyotype (47,XXY/46,XY), higher grade aneuploidies (48,XXXY or 48,XXYY) or a structurally abnormal X chromosome (e.g., 47,iXq,Y), with mosaic cases originating a less severe KS phenotype [3,4,[8][9][10][11][12]. ...
... About 80-90% of KS cases present a non-mosaic karyotype (47,XXY), while the remaining 10-20% evidence a mosaic karyotype (47,XXY/46,XY), higher grade aneuploidies (48,XXXY or 48,XXYY) or a structurally abnormal X chromosome (e.g., 47,iXq,Y), with mosaic cases originating a less severe KS phenotype [3,4,[8][9][10][11][12]. ...
Klinefelter syndrome (KS), caused by the presence of an extra X chromosome, is the most prevalent chromosomal sexual anomaly, with an estimated incidence of 1:500/1000 per male live birth (karyotype 47,XXY). High stature, tiny testicles, small penis, gynecomastia, feminine body proportions and hair, visceral obesity, and testicular failure are all symptoms of KS. Endocrine (osteoporosis, obesity, diabetes), musculoskeletal, cardiovascular, autoimmune disorders, cancer, neurocognitive disabilities, and infertility are also outcomes of KS. Causal theories are discussed in addition to hormonal characteristics and testicular histology. The retrieval of spermatozoa from the testicles for subsequent use in assisted reproduction treatments is discussed in the final sections. Despite testicular atrophy, reproductive treatments allow excellent results, with rates of 40–60% of spermatozoa recovery, 60% of clinical pregnancy, and 50% of newborns. This is followed by a review on the predictive factors for successful sperm retrieval. The risks of passing on the genetic defect to children are also discussed. Although the risk is low (0.63%) when compared to the general population (0.5–1%), patients should be informed about embryo selection through pre-implantation genetic testing (avoids clinical termination of pregnancy). Finally, readers are directed to a number of reviews where they can enhance their understanding of comprehensive diagnosis, clinical care, and fertility preservation.
... Reasons for male infertility are manifold and include deviant transcript and protein abundances in the testis and sperm [4][5][6]. Chromosomal aberrations, such as Klinefelter syndrome (47,XXY), are also well-recognized to negatively affect male fertility [7]. Changes in chromosome structure can elicit infertility too. ...
Deciphering the functional relationships of genes resulting from genome-wide screens for polymorphisms that are associated with phenotypic variations can be challenging. However, given the common association with certain phenotypes, a functional link should exist. We have tested this prediction in newly sequenced exomes of altogether 100 men representing different states of fertility. Fertile subjects presented with normal semen parameters and had naturally fathered offspring. In contrast, infertile probands were involuntarily childless and had reduced sperm quantity and quality. Genome-wide association study (GWAS) linked twelve non-synonymous single-nucleotide polymorphisms (SNPs) to fertility variation between both cohorts. The SNPs localized to nine genes for which previous evidence is in line with a role in male fertility maintenance: ANAPC1, CES1, FAM131C, HLA-DRB1, KMT2C, NOMO1, SAA1, SRGAP2, and SUSD2. Most of the SNPs residing in these genes imply amino acid exchanges that should only moderately affect protein functionality. In addition, proteins encoded by genes from present GWAS occupied peripheral positions in a protein–protein interaction network, the backbone of which consisted of genes listed in the Online Mendelian Inheritance in Man (OMIM) database for their implication in male infertility. Suggestive of an indirect impact on male fertility, the genes focused were indeed linked to each other, albeit mediated by other interactants. Thus, the chances of identifying a central player in male infertility by GWAS could be limited in general. Furthermore, the SNPs determined and the genes containing these might prove to have potential as biomarkers in the diagnosis of male fertility.
... Klinefelter syndrome is a sex chromosomal aneuploidy in males, which may not be diagnosed at birth. Klinefelter syndrome is primarily associated with hypergonadotropic hypogonadism, which can cause a signi cantly varying presentation of physical and psychological symptoms (1)(2)(3)(4)(5). The prevalence is reported to be 15 (range: 8. 5-22.3) per 10,000 males (6). ...
... Studies show increased mortality (5,11,12) and morbidity (2,5,8,13) among adults with Klinefelter syndrome and indicates, that some of the physical and cognitive challenges can occur from the early childhood (14). Studies describing morbidity and mortality in childhood for children diagnosed with Klinefelter syndrome are limited, often based on small populations and typically focusing on the speci c causes and not the burden of disease compared to the background population (4,(15)(16)(17)(18)(19)(20). ...
Background
Klinefelter syndrome is a congenital chromosomal anomaly, where males have an extra X-chromosome. The syndrome may be associated with hypergonadotropic hypogonadism and many are late or undiagnosed. This European, population-based data-linkage cohort study was part of the EUROlinkCAT project and investigated the burden of disease for the first ten years of life for European children diagnosed with Klinefelter syndrome.
Results
Thirteen national and regional population-based registries in ten countries from the European surveillance of congenital anomalies (EUROCAT) network participated. Data for live born children born in 1995-2014 and diagnosed with Klinefelter syndrome prenatally or during infancy were linked to mortality and hospital records. Data for liveborn children born with any congenital anomaly and children without a congenital anomaly (reference children) were included for comparison on morbidity. Out of 5.8 million live born children 278 were diagnosed with Klinefelter syndrome in the 13 registry areas, 96.8% survived the first 5 year of life, 64.7% (95% CI 51.8;75.0) were admitted to hospital during the first year with a median length of stay of 3.9 (95% CI 3.0;4.7) days, 10.8% (95% CI 6.9;16.4) had a hospital stay of ≥10 days and 12.3% (95% CI 7.1;18.9) underwent surgery. In the age group 1-4 years of age 53.5% (95% CI 41.2;64.4) were admitted to hospital, the median length of stay decreased to 0.7 (95% CI 0.3;1.1) days and 6.3% (95% CI 2.6;12.3) had a hospital stay of ≥ 10 days.
Conclusions
More children diagnosed prenatally or in infancy with Klinefelter syndrome were hospitalised and underwent more surgery compared to reference children, while less were hospitalised and fewer had surgery than all children with any other congenital anomaly. Thus, the burden of disease was increased for children diagnosed prenatally or in infancy with Klinefelter syndrome but decreased overall after the first year of life.
... Early in the course of double aneuploidy, the clinical picture is almost always compatible with autosomal chromosome aneuploidy. It is evident from this case and most published reports of 48,XXY,+21 that they exhibit features typical of Down syndrome alone, since the features of Klinefelter syndrome are not evident until after pubertal development, as one would expect [15]. ...
... Boys with KS may have micropenis or cryptorchism at birth as a result of intrauterine hypogonadism. But, the majority of boys with Klinefelter syndrome appear similar to boys with normal karyotypes, so the disorder is typically discovered as adults when infertility or gynecomastia is a common symptom [15,17]. ...
... At age two, he showed blunted response to HCG stimulation. In these cases, thorough evaluation at puberty is necessary, since they may have elevated levels of gonadotrophins; follicle-stimulating hormone (FSH), luteinizing hormone (LH), and estradiol (E2) with low levels of testosterone, and the testes may grow a little but shrink subsequently [15]. ...
Double aneuploidies, such as Down syndrome and sex chromosome aneuploidies, are relatively rare. One rare form of double aneuploidy, Down-Klinefelter syndrome, is described here. The phenotypic characteristics of a three-year-old child showed the presence of features typical of Down syndrome. He had a global developmental delay, small testes, and diabetes mellitus by 18 months of age. Regardless of the presenting clinical features, karyotyping should be performed in all patients with suspected Down syndrome. In Down-Klinefelter syndrome, anticipatory phenotype goes beyond the sum of individual syndromic characteristics.
... The loss of germ cells, which begins in foetal life and accelerates through puberty, leads to fibrosis and hyalinization of seminiferous tubules and relative hyperplasia of Leydig cells. Those processes result in characteristic features of KS such as small, firm testes, hypergonadotropic hypogonadism, and the absence of spermatogenesis [4,5]. ...
Klinefelter syndrome is the most commonly reported sex chromosome abnormality. It is heavily underdiagnosed due to the substantial variability of clinical presentations but is generally characterized by small, firm testes, hypergonadotropic hypogonadism, and the absence of spermatogenesis. Most patients with Klinefelter syndrome have a 47,XXY genotype. If they present with mosaicism, two different cell lines are usually identified, an aneuploid 47,XXY cell line and a normal male 46,XY cell line. There are very few cases of 47,XXY mosaicism with the additional female cell line 46,XX described in the literature. We report a case of an adolescent with the male phenotype and a rare variant mosaic 47,XXY/46,XX karyotype who presented with painless bilateral gynaecomastia. 47,XXY and 46,XX mosaic cell lines were identified with GTG-banding and further characterized using fluorescent in situ hybridization. We summarized the available clinical presentations of reported
male patients with 47,XXY/46,XX mosaicism. To improve the clinical management and quality of
life in individuals with rare and cryptic genomic imbalances, the genetic diagnosis would need to be
extended to atypical cases.
... 9,10 Klinefelter syndrome (47,XXY) is the most common sex chromosomal disorder in individuals presumed male at birth, affecting 0.02%−0.22% of the population. [11][12][13] Klinefelter syndrome is a significantly underdiagnosed condition with estimates suggesting only 25%−50% of individuals are diagnosed. 14,15 Diagnosis is frequently made in adulthood during fertility assessment. ...
... 14,27,46 However, it is important to note that Klinefelter syndrome is thought to be underdiagnosed and even when diagnosed, it is usually delayed and post-pubertal. 13,14,46,47 Studies have suggested that 50%−75% of Klinefelter syndrome is not diagnosed. 46,48 Given the underdiagnosis in the general population, pre-natal screening programs can also be considered. ...
Objective
Previous studies have suggested a higher prevalence of Klinefelter syndrome amongst transgender individuals. We undertook a systematic review to determine the prevalence of Klinefelter syndrome amongst transgender individuals presumed male at birth and summarise the clinical features and potential treatment implications for individuals with Klinefelter syndrome commencing gender-affirming hormone therapy.
Design
Using preferred reporting items for systematic review and meta-analysis guidelines, we searched EMBASE, MEDLINE and the Cochrane Central Register of Controlled Trials (CENTRAL) up to December 31, 2021. All studies reporting on the prevalence or clinical features of transgender individuals with Klinefelter syndrome were included. This study is registered with the International Prospective Register of Systematic Reviews, number CRD42021227916.
Results
Our search strategy retrieved 11 cohort studies comprising 1376 transgender individuals. In all, 14 of 1376 (1.02%) individuals were diagnosed with Klinefelter syndrome. Based on the 7 studies in which karyotype was undertaken in all individuals, the prevalence is 9/1013 (0.88%; 95% CI, 0.41%-1.68%). Case reports highlight unique treatment considerations in this population, including azoospermia, venous thromboembolism, and monitoring of breast cancer and bone health.
Conclusions
Compared to the general population, observational studies document a higher prevalence of Klinefelter syndrome amongst transgender individuals, though underdiagnosis in the general population limits conclusions. Routine karyotype in transgender people initiating gender-affirming hormone therapy is not supported unless clinical features of Klinefelter syndrome, such as small testicular volume, or hypergonadotropic hypogonadism are present. Transgender individuals with Klinefelter syndrome need to manage a unique risk profile if they desire feminising gender-affirming hormone therapy.
... The majority of these patients have a karyotype of 47, XXY, with other variations such as 48, XXXY, 48, XXYY, and 49, XXXXY being rare and occurring in a minority of cases [1]. It is the most common sex chromosome disorder, with a prevalence of 1 in every 660 males [2,3]. But despite being this prevalent, only a small fraction of these patients get diagnosed, with some estimate that 70% of KS patients will remain oblivious about their condition [4], which can have dire consequences as early recognition and management play a vital role in the prevention of the disease complications chiefly primary hypogonadism. ...
... In male patients with persistent or transient elevated ST with negative CFTR gene analysis and in absence of CF typical symptoms, KS diagnosis has to be considered, performing karyotype analysis. The causes that may explain the increase of ST in KS are still unknown: we may only speculate, according to literature evidences, that the higher body size of these subjects and the severe deficiency of androgens [26,27] during puberty may influence the activity of sweat glands causing a persistent SC alteration. Finally, for the two cases treated with PEG, it is well known that some formulations of the drug contain salts and thus they may alter the ST. ...
Background
The sweat chloride test (ST) is the gold standard for cystic fibrosis (CF) diagnosis in symptomatic patients, within the newborn screening and in the follow-up of CF patients during molecular therapies. However, false positives have been reported in patients with different diseases. We describe and discuss 4 cases due to different clinical conditions in which we recorded false positive ST, and the test remained altered for a period of varying length.
Cases presentation
Case 1: Eight months old female child suffering from constipation, recurrent vomiting and failure to thrive, family history of recurrent pancreatitis without mutations in the PRSS1 and SPINK1 genes. Both ST and fecal elastase were altered although no CFTR gene mutations were found. Due to rapid clinical deterioration, celiac disease was suspected and diagnosed by laboratory tests and intestinal biopsy. After 2 weeks of gluten-free diet ST and fecal elastase normalized.
Case 2: 14 months old male suffering from bilateral renal dysplasia, episodes of metabolic alkalosis, recurrent respiratory infections and recurrent vomiting. The child had more ST positives, but no CFTR mutations were found. During follow-up, he developed sensorineural hearing loss and an atrial septic defect was found. Finally, a diagnosis of Klinefelter was made, but the ST normalized several years later.
Case 3 and 4: Two boys with stubborn constipation and fecal occlusion treated with Poly Ethylene Glycol (PEG) with salts showed pathological ST. The test returned normal a few days after stopping treatment.
Conclusions
We hypotesized the possible causes of ST alteration in these conditions: in celiac disease it could be due to a transient dysregulation of the aquaporins, rapidly reversed by the diet; in Klinefelter, it may be due to stable pubertal hypoandrogenism; while, the PEG formulation itself contains salts that can temporarily alter ST.
