Classical Klinefelter Syndrome Research Articles

FRI452 A Rare Case of Klinefelter Syndrome, 48XXYY

Abstract Disclosure: P. Kachhadia: None. S. Khan: None. S. Aldasouqi: None. A. Abu Limon: None. Introduction: Klinefelter Syndrome (KS), 47XXY, is the most commonly seen chromosomal abnormality causing infertility, or primary hypogonadism. Other chromosomal variants are rare. We present a very rare case of nondisjunction of the sex chromosome resulting in a 48XXYY KS variant. Case Presentation: The patient is a 45-year-old male was referred to our clinic for evaluation of early onset osteoporosis. The patient was accompanied by his sister, given his cognitive delay. On initial physical exam, there was a concern about acromegaly with signs of frontal bossing, increased hand size, increased ring size and increased shoe size. More recent pictures of the patient showed significant changes in his facial appearance from few years prior. Other symptoms included night sweats. Physical exam revealed decreased testicular volume (less than 3mL bilaterally). Pituitary labs showed elevated prolactin, elevated LH, FSH and low free and total testosterone. GH, IGF-1 levels were within normal range. Chromosomal analysis showed an unexpected pattern of 48XXYY. In addition, MRI of the pituitary was done which showed increased infundibular stalk and increase in size of the pituitary gland which was thought to be secondary to pituitary microadenoma. DEXA scan confirmed osteoporosis. Patient was treated with testosterone injections and alendronate. The rationale for alendronate therapy was considered as a bridge to prevent fractures while the bone density would expectedly improve with androgen therapy, over time. Discussion: Although KS is commonly seen at a frequency of 1:500-1:1000 males, less common and variable phenotypical presentations can occur and can lead to a delayed diagnosis. The reason for the delay of diagnosis in these rare KS variants is the cognitive impairment which leads to delayed evaluation of fertility or hypogonadism, as contrasted to patients with the common variant, KS 47XXY. Additionally, unlike the classic KS variant, these rare variants are often associated with learning disabilities and gross bony features. Conclusion: Clinicians should be familiar with different clinical presentations of the less common KS genetic variants, in contrast to classical KS variants. Patients with classical KS typically present early in view of recognizable complaints of infertility, while patients with the less common KS variants may not present early on due to cognitive delay. Thus, familiarity with the additional manifestations of the less common KS variants (e.g., gross bony features) can help clinicians to suspect the possibility of these variants, prompting chromosomal analysis for further evaluation in such patients. Presentation Date: Friday, June 16, 2023

A Prospective Study on Klinefelter Syndrome: A Basket of Multiple Systemic Disorders in a Tertiary Care Hospital

Background: When one or more extra X chromosome is added to a normal male karyotype (46-XY), then a new aneuploidy appears called Klinefelter Syndrome (KS). Every day approximately more than 50 new such cases are added in the male population of India. Traditionally they are lean, thin, tall, azoospermic, hypogonadic, infertile males with low social and educational profile. As the age advances level of testosterone decreases and many new symptoms of multiple systemic disorders appear in these cases. Methods: A well designed questionnaire of infertile males attending the above- mentioned OPD’s was filled with history, clinical examination and semen analysis (twice as per the WHO criteria). Results: In our series of 500 azoospermic males, we encountered 56 classical KS cases (11.2 %) of 47-XXY karyotype, who were hypergonadotrophic hypogonadic and diagnosed with multiple diseases when evaluated in detail. Conclusions: Hence, every KS must receive androgen replacement therapy, which should begin at puberty and continue for lifelong that helps in preventing the development of high comorbidity rate and premature deaths because these are very high in such condition as compared to normal male population.

Endocrine and metabolic evaluation of classic Klinefelter syndrome and high-grade aneuploidies of sexual chromosomes with male phenotype: are they different clinical conditions?

Klinefelter syndrome (KS) is the most common sex chromosome aneuploidy in males. As well as classic KS, less frequent higher-grade aneuploidies (HGAs) are also possible. While KS and HGAs both involve testicular dysgenesis with hypergonadotropic hypogonadism, they differ in many clinical features. The aim of this study was to investigate the endocrinal and metabolic differences between KS and HGAs. Cross-sectional, case-control study. 88 patients with KS, 24 with an HGA and 60 healthy controls. Given the known age-related differences all subjects were divided by age into subgroups 1, 2 and 3. Pituitary, thyroid, gonadal and adrenal functions were investigated in all subjects. Metabolic aspects were only evaluated in subjects in subgroups 2 and 3. FT4 and FT3 levels were significantly higher in HGA than in KS patients in subgroups 1 and 2; in subgroup 3, FT4 was significantly higher in controls than in patients. Thyroglobulin was significantly higher in HGA patients in subgroup 1 than in KS patients and controls. Hypergonadotropic hypogonadism was confirmed in both KS and HGA patients, but was more precocious in the latter, as demonstrated by the earlier increase in gonadotropins and the decrease in testosterone, DHEA-S and inhibin B. Prolactin was significantly higher in HGA patients, starting from subgroup 2. Total and LDL cholesterol were significantly higher in HGA patients than in KS patients and controls, while HDL cholesterol was higher in controls than in patients. KS and HGAs should be considered as two distinct conditions.

Sperm Retrieval in Patients with Klinefelter Syndrome: A Skewed Regression Model Analysis.

BackgroundThe most common chromosomal abnormality due to non-obstructive azoospermia (NOA) is Klinefelter syndrome (KS) which occurs in 1-1.72 out of 500-1000 male infants. The probability of retrieving sperm as the outcome could be asymmetrically different between patients with and without KS, therefore logistic regression analysis is not a well-qualified test for this type of data. This study has been designed to evaluate skewed regression model analysis for data collected from microsurgical testicular sperm extraction (micro-TESE) among azoospermic patients with and without non-mosaic KS syndrome.Materials and MethodsThis cohort study compared the micro-TESE outcome between 134 men with classic KS and 537 men with NOA and normal karyotype who were referred to Royan Institute between 2009 and 2011. In addition to our main outcome, which was sperm retrieval, we also used logistic and skewed regression analyses to compare the following demographic and hormonal factors: age, level of follicle stimulating hormone (FSH), luteinizing hormone (LH), and testosterone between the two groups.ResultsA comparison of the micro-TESE between the KS and control groups showed a success rate of 28.4% (38/134) for the KS group and 22.2% (119/537) for the control group. In the KS group, a significantly difference (P<0.001) existed between testosterone levels for the successful sperm retrieval group (3.4 ± 0.48 mg/mL) compared to the unsuccessful sperm retrieval group (2.33 ± 0.23 mg/mL). The index for quasi Akaike information criterion (QAIC) had a goodness of fit of 74 for the skewed model which was lower than logistic regression (QAIC=85).ConclusionAccording to the results, skewed regression is more efficient in estimating sperm retrieval success when the data from patients with KS are analyzed. This finding should be investigated by conducting additional studies with different data structures.

48, XXYY Genotype: Case Report of a Rare Clinical Syndrome

Klinefelter Syndrome (KS) is the most common sex chromosomal disorder which occurs in approximately 1 per 500 live born male births [1]. The characteristic clinical features of KS with the classic 47, XXY karyotype is well recognized which includes seminiferous tubule dysgenesis, androgen deficiency, cognitive and behavioral dysfunction, increased risk of autoimmune disorders, thromboembolic disease and cancer [2]. With each additional X chromosome there is progressive divergence from the normal with increased frequency of phenotypic, endocrine and structural abnormalities [3]. Poly X-syndrome, often described in literature as a variant of KS, is much rarely reported with a prevalence of 1:18,000-1:100,000 male births and has more pronounced congenital malformations and associated medical comorbidities [4]. We describe a case of a patient who had a formal diagnosis of classic KS from a very young age of 14, presented with not only behavioral and cognitive impairment but also with a wide spectrum of medical complications and further identified on reassessment as XXYY genotype.

Mild Deficits of Cortical Bone in Young Adults With Klinefelter Syndrome or Anorchia Treated With Testosterone.

There are currently no data evaluating volumetric bone mineral density (BMD), bone geometry, and body composition in adults with Klinefelter syndrome (KS) or anorchia who have been treated with T from adolescence. To determine volumetric BMD, bone geometry using peripheral quantitative computed tomography (pQCT), and body composition using dual-energy x-ray absorptiometry (DXA) in men with classical KS or anorchia treated with T from adolescence (age, <16 y), compared with matched controls. Twenty subjects (12 KS, eight anorchia) and 20 controls underwent a pQCT (66% tibia, 4% radius) and total body DXA. Using adjusted regression models, there was reduced tibial cortical area (95% confidence interval [CI], -88.8 to -4.4 mm(2); P = .03) and thickness (95% CI, -0.98 to -0.10 mm; P = .02) in subjects. All other bone parameters were similar between groups. Subjects had significantly higher fat mass (95% CI, 1.6 to 14.9 kg; P = .02), trunk:leg fat ratio (95% CI, 0.09 to 0.60; P = .01), and visceral adipose mass (95% CI, 0.057 to 0.283 kg; P = .004). Lean mass was similar in both groups. Lean mass was positively associated with tibial cortical area and radial total, trabecular, and volumetric density (P < .05). This first report using pQCT and DXA in men with KS or anorchia treated from adolescence showed normal volumetric BMD but reduction in cortical area and thickness, only at the 66% tibia site. Our study also demonstrated for the first time that men with KS or anorchia have increased visceral adiposity despite T treatment.

Comparison of Sperm Retrieval and Intracytoplasmic Sperm Injection Outcome in Patients With and Without Klinefelter Syndrome

To evaluate microsurgical testicular sperm extraction (micro-TESE) and intracytoplasmic sperm injection (ICSI) treatment in patients with non-mosaic Klinefelter syndrome (KS). We retrospectively evaluated the micro-TESE/ICSI performance in 134 patients with classic KS and 537 men with nonobstructive azoospermia (NOA) and normal karyotype referred to Royan Institute between 2009 and 2011. The patients were divided into 2 groups according to micro-TESE outcome. Several factors, including patients' age, level of follicle stimulating hormone (FSH), luteinizing hormone (LH), and testosterone, were compared between the 2 groups. Sperm retrieval rate by micro-TESE in the KS and control groups were 28.4% (38/134) and 22.2% (119/537), respectively. In the KS group, the mean age of patients with successful sperm retrieval of spermatozoa was significantly lower than those with negative results (30.0 ± 0.65 vs 33.68 ± 0.6 year, P= .001) and comparison of laboratory parameters between the 2 groups showed that the level of testosterone was significantly higher in patients with successful sperm retrieval (3.4 ± 0.48 vs 2.33 ± 0.23 ng/mL, P<.001). The fertilization rate was significantly higher in the KS group than the control group (28% vs 21%, P= .038). Also, live birth rate per embryo transfer was higher in the KS group, but it was not significant (13% vs 3%, P= .05). This study of sperm recovery and ICSI outcome in men with and without KS shows that micro-TESE/ICSI is a successful intervention for the majority of men with KS.

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

This study aims to provide further insight into the phenotypic heterogeneity of Klinefelter syndrome (KS) by presenting clinical, hormonal, and genetic data from a large series of Egyptian infertile patients with KS. A retrospective case series of KS patients was studied over a period from January 2003 to April 2010. All patients underwent a complete history and physical examination; color duplex examination; semen analysis; measurement of total testosterone (T), follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), and prolactin (PRL); and chromosomal typing. Mosaic KS diagnosis was confirmed by fluorescence in situ hybridization. The series included 216 KS patients (198 nonmosaic, 16 mosaic, and 2 KS variants). Typical clinical signs of hypoandrogenism were observed in 86% of patients. Gynecomastia affected 20.8% of the patients. Eunuchoidal body proportions, with arm span exceeding height and lower segment length exceeding upper segment length, were detected in 43.9% and 64.4% of the patients, respectively. In all patients, a reduction in testicular size and azoospermia were detected. Normal levels of T, FSH, LH, E2, and PRL were detected in 44.5%, 3.7%, 3.3%, 93.5%, and 91.2% of patients, respectively. Differences were not significant between patients with classic KS and those with mosaic KS in terms of the frequency of clinical signs of hypoandrogenism, gynecomastia, low T concentrations, or high concentrations of FSH, LH, E2, and PRL (all P > .05). The results of the current study emphasize the heterogeneous clinical, hormonal, and genetic phenotype of infertile KS patients. Our findings support the usefulness of cytogenetic studies in infertile patients showing small testicular size and azoospermia, regardless of the presence of other clinical or endocrine findings.

Unusual endocrine and somatic phenotypic abnormalities in a 14-year-old boy with classic Klinefelter syndrome (47,XXY)

Unusual endocrine and somatic phenotypic abnormalities in a 14-year-old boy with classic Klinefelter syndrome (47,XXY)

Brain Magnetic Resonance Imaging Findings in 49,XXXXY Syndrome

Klinefelter syndrome is a chromosomal disorder characterized by one or more supernumerary X chromosomes, in addition to the normal 46,XY male karyotype. Whereas classic Klinefelter syndrome (47,XXY) occurs in 1:400 births, the most severe Klinefelter variant (49,XXXXY) occurs in only 1:85,000 births. The degree of cognitive impairment, specific skeletal changes, and genital abnormalities in Klinefelter syndrome variants is thought to correlate with the number of additional X-chromosomes present. Magnetic resonance imaging studies in individuals with classic Klinefelter syndrome show smaller brain volumes, but magnetic resonance imaging data are lacking for individuals with rarer and more severe Klinefelter variants. We present case reports and magnetic resonance imaging studies on 3 individuals with 49,XXXXY. All 3 patients exhibited varying degrees of volume loss and abnormalities in white matter. Changes in white matter may represent a specific finding in patients with severe Klinefelter variants such as 49,XXXXY, and karyotype analysis should be considered in patients with unexplained white-matter disease, especially when developmental delay or genital abnormalities are present.

Preserved fertility in a non-mosaic Klinefelter patient with a mutation in the fibroblast growth factor receptor 3 gene: Case Report

Patients with Klinefelter syndrome (47,XXY) are characterized by eunuchoid body proportions, gynaecomastia, small firm testes and azoospermia. We describe a Klinefelter patient (non-mosaic 47,XXY karyotype) who was heterozygous for the classical 1138G>A mutation in the fibroblast growth factor receptor 3 (FGFR3) gene, which is a gain-of-function mutation resulting in achondroplasia. The patient had phenotypic characteristics of achondroplasia (e.g. short limbed dwarfism and frontal bossing). Testicular volume was 8 ml at 27 years of age and repeated semen samples showed sperm concentrations of 0.175 million/ml. Serum FSH levels were elevated (21.7 IU/l) compared to normal age-matched healthy male controls and patients with non-mosaic Klinefelter syndrome, and inhibin B levels were low-normal, in contrast to the usually undetectable inhibin B levels in adult Klinefelter patients. The patient fathered a child from a spontaneous pregnancy. The observed testicular size and function in our patient contrast the typical findings in classical Klinefelter syndrome. We speculate that the alteration of FGFR3 protein function in our Klinefelter patient alleviated the destruction of the seminiferous tubules and may suggest that the fibroblast growth factor family has a pleiotrophic function in human spermatogonia, which physiologically express FGFR3.

Analysis of Meiosis in Intratesticular Germ Cells from Subjects Affected by Classic Klinefelter's Syndrome

Analysis of Meiosis in Intratesticular Germ Cells from Subjects Affected by Classic Klinefelter's Syndrome

PARANOID SCHIZOPHRENIA IN A PATIENT WITH KLINEFELTER'S SYNDROME.

A case is described of a classic Klinefelter's syndrome associated with a florid attack of schizophrenia. The patient also possessed normal intelligence and had exhibited interesting psychosexual deviations. The authors are of the opinion that the concurrence of Klinefelter's syndrome with schizophrenia is purely coincidental.