Diagnosis Of Klinefelter Syndrome Research Articles

6626 Fertility considerations in Klinefelter Syndrome complicated by hypogonadotrophic hypogonadism

Abstract Disclosure: M. Govinna: None. S. Sarlos: None. C.A. Allan: None. R. Giri: None. Background: Klinefelter syndrome (KS) remains underdiagnosed with less than 50% of men ever diagnosed and >90% of diagnoses only occurring when fertility is sought. MicroTESE (microscopic testicular sperm extraction) is now successful in 47-69% [1]. Optimal timing of the procedure is uncertain. Case: A 14-year-old male student with a history of renal stones (normal genitourinary tract anatomy) and anxiety presented with a six-day history of new onset headaches and transient visual blurring. MRI scan showed a 2.1cm pituitary lesion with local mass effect and minimal compression of the optic chiasm. Pre-operative pituitary panel: FSH 29.8 IU/L (1.2 - 5.2 IU/L); LH 8.8 IU/L (2.0 - 8.0 IU/L); testosterone 10.9 nmol/L (0.7 - 17.6 nmol/L). Remainder of anterior pituitary function was normal; no AVP deficiency. On examination, Tanner stage P4 G4, testicular volumes 5-6ml (right) and 6-8ml (left) (expected range 15-20ml). Height 175cm (75th centile) and weight 60.1kg (63rd centile). Transsphenoidal resection (TSS) of the pituitary lesion was performed. Intraoperative appearances were suggestive of craniopharyngioma adherent to the pituitary stalk, with stalk transection to achieve complete resection. Post-operatively AVP-deficiency, hypocortisolism and secondary hypothyroidism required replacement therapy. Histopathology was subsequently consistent with Rathke’s cleft cyst. Karyotype testing confirmed 47 XXY genotype (Klinefelter syndrome). Post-TSS FSH and LH levels were 0.7IU/L (1.2 - 5.2 IU/L) and 0.3 IU/L (2.0 - 8.0 IU/L); with testosterone <0.1 nmol/L (0.7 - 17.6 nmol/L), consistent with hypogonadotrophic hypogonadism superimposed on a background of primary hypogonadism. Testosterone replacement therapy was commenced following discussion regarding potential future fertility options. Discussion: This diagnosis of KS highlights the importance of thorough assessment of pubertal development and testicular examination. Small testes with hypergonadotrophic hypogonadism in the context of pituitary pathology should trigger further assessment. Fertility preservation procedures in prepubertal and adolescent boys with KS remain controversial [2]. This patient represents a unique scenario whereby he is LH and FSH deficient post TSS. Whilst prior treatment with hCG does not increase sperm retrieval in non-mosaic KS [3] there may be a role for gonadotrophin therapy prior to undertaking microTESE in our patient. To date, there are no reported cases.

6626 Fertility considerations in Klinefelter Syndrome complicated by hypogonadotrophic hypogonadism

Abstract Disclosure: M. Govinna: None. S. Sarlos: None. C.A. Allan: None. R. Giri: None. Background: Klinefelter syndrome (KS) remains underdiagnosed with less than 50% of men ever diagnosed and >90% of diagnoses only occurring when fertility is sought. MicroTESE (microscopic testicular sperm extraction) is now successful in 47-69% [1]. Optimal timing of the procedure is uncertain. Case: A 14-year-old male student with a history of renal stones (normal genitourinary tract anatomy) and anxiety presented with a six-day history of new onset headaches and transient visual blurring. MRI scan showed a 2.1cm pituitary lesion with local mass effect and minimal compression of the optic chiasm. Pre-operative pituitary panel: FSH 29.8 IU/L (1.2 - 5.2 IU/L); LH 8.8 IU/L (2.0 - 8.0 IU/L); testosterone 10.9 nmol/L (0.7 - 17.6 nmol/L). Remainder of anterior pituitary function was normal; no AVP deficiency. On examination, Tanner stage P4 G4, testicular volumes 5-6ml (right) and 6-8ml (left) (expected range 15-20ml). Height 175cm (75th centile) and weight 60.1kg (63rd centile). Transsphenoidal resection (TSS) of the pituitary lesion was performed. Intraoperative appearances were suggestive of craniopharyngioma adherent to the pituitary stalk, with stalk transection to achieve complete resection. Post-operatively AVP-deficiency, hypocortisolism and secondary hypothyroidism required replacement therapy. Histopathology was subsequently consistent with Rathke’s cleft cyst. Karyotype testing confirmed 47 XXY genotype (Klinefelter syndrome). Post-TSS FSH and LH levels were 0.7IU/L (1.2 - 5.2 IU/L) and 0.3 IU/L (2.0 - 8.0 IU/L); with testosterone <0.1 nmol/L (0.7 - 17.6 nmol/L), consistent with hypogonadotrophic hypogonadism superimposed on a background of primary hypogonadism. Testosterone replacement therapy was commenced following discussion regarding potential future fertility options. Discussion: This diagnosis of KS highlights the importance of thorough assessment of pubertal development and testicular examination. Small testes with hypergonadotrophic hypogonadism in the context of pituitary pathology should trigger further assessment. Fertility preservation procedures in prepubertal and adolescent boys with KS remain controversial [2]. This patient represents a unique scenario whereby he is LH and FSH deficient post TSS. Whilst prior treatment with hCG does not increase sperm retrieval in non-mosaic KS [3] there may be a role for gonadotrophin therapy prior to undertaking microTESE in our patient. To date, there are no reported cases.

A rare case of adult-onset spastic paraparesis associated with Klinefelter syndrome

ReportThe rare association of Klinefelter syndrome and the clinical presentation of a late onset chronic progressive spastic paresis.Clinical Presentation and GeneticsAn infertile, 61-year-old man, presented with late adult onset of gait problems, deep muscle pain, and bladder problems. He presented for the first time, years after onset with a spastic paraparesis with high arched feet. His parents had already died, but the patient described high arched feet with his mother. There is no further certain information about the parents. After thorough investigation, an additional X chromosome was found, whereafter the diagnosis of Klinefelter syndrome could be made. Other acquired and genetic causes for spastic paraparesis or hereditary motor neuropathy are excluded.ConclusionThis rare case, together with three other literature reports by Sasaki (Intern Med 58(3):437–440, 2019), Sajra (Med Arh 61(1):52–53, 2007) and Matsubara et al., (J Neurol Neurosurg Psychiatry 57(5):640–642, 1994). suggests that Klinefelter syndrome can be associated with spastic paraparesis, besides the other various neuropsychiatric symptoms that are more commonly described.

(070) Testosterone Therapy in Men with Klinefelter Syndrome: Analysis of a Global Federated Research Network

Abstract Introduction Klinefelter syndrome (KS) is a genetic condition in which a male is born with an extra X-chromosome and is one of the on-label indications for testosterone replacement therapy (TRT). The prevalence of testosterone deficiency in men with KS is difficult to predict and not well described in the literature. Furthermore, there is no previous literature detailing the rates of TRT prescription in men diagnosed with KS. Objective We aimed to determine the rates of hypogonadism and prescription of TRT in men with KS using a large, federated research database. We hypothesized that men with KS are undertreated for testosterone deficiency with TRT due to a combination of factors including a poor understanding of hypogonadism in this population and neurocognitive issues leading to delay in seeking treatment for hypogonadism. Methods We queried TriNetX, a large, multicenter electronic health record database, to identify all men with a diagnosis of Klinefelter syndrome (ICD-10-CM Q98.4) excluding men with prescription of TRT prior to diagnosis of KS or a diagnosis of KS more than 20 years ago. Descriptive analysis on associated comorbidities and demographic characteristics was performed. We then filtered the initial cohort to find men who received a laboratory measurement of testosterone level on the day of diagnosis with KS or later. Prevalence of testosterone deficiency was determined as defined by testosterone level < 300 ng/dl. The primary outcome of the study was prescription of any of the following forms of TRT on the day of diagnosis or later using associated medication codes: testosterone, testosterone 17-phenylpropionate, testosterone enanthate, testosterone cypionate, testosterone undecanoate. Rates of TRT prescription were determined for both the initial cohort and the hypogonadal subgroup. Results There were 5,437 total men with diagnosis of KS. A total of 1,581 men with KS received laboratory measurement of testosterone level, 1,113 (70.4%) of whom were hypogonadal. Mean testosterone level in this group was 354 ng/dL [50 – 658]. Of the 1,113 men found to be hypogonadal, only 657 (59.0%) men were given prescription for TRT. Conclusions This is the first study to evaluate TRT prescribing habits in men with KS. In this large, retrospective study, TRT was under-prescribed in men with KS. Further studies are needed to corroborate these findings and to evaluate the barriers to receiving care in this population. Disclosure No

Clinicopathological characteristics of Klinefelter syndrome: a testicular biopsy analysis of 87 cases

Objective: To investigate the clinicopathological characteristics of testicular biopsies from Klinefelter syndrome (KS) patients. Methods: The testicular biopsy specimens of 87 patients with KS (a total of 107 biopsy specimens) were collected from the Department of Pathology, Peking University Third Hospital, Beijing, China from January 2017 to July 2022. All patients were diagnosed as KS by peripheral blood karyotyping analysis. The testicular histopathologic features, testicular volume and hormone levels were evaluated retrospectively. The histopathologic analysis was used to assess the quantity and morphology of Leydig cells, the spermatogenic state of seminiferous tubules, the thickening of the basement membrane of seminiferous tubules and the changes of stroma. Results: Leydig cell proliferative nodules were seen in 95.3% (102/107) of KS testicular biopsy tissues. The eosinophilic inclusion bodies and lipofuscin in Leydig cells were found in 52.3% (56/107) and 57.9% (62/107) of specimens, respectively. The Sertoli cell only seminiferous tubules and the hyalinized tubules were found in 66.4% (71/107) and 76.6% (82/107) of the examined tissues, respectively. The tubules with complete spermatogenic arrest were found in 15.9% (17/107) of specimens, and 5.6% (6/107) of the specimens showed low spermatogenesis or incomplete spermatogenic arrest. In 85.0% (91/107) of the specimens, increased thick-walled small vessels with hyaline degeneration were identified. Conclusions: The most common features of KS testicular specimens are Leydig cell proliferative nodules, hyaline degeneration of seminiferous tubules and proliferation of thick-walled blood vessels. Testicular biopsy specimens of KS are rare. The pathologists can make a tentative diagnosis of KS based on the histological findings, combined with the ultrasound and laboratory results, which is helpful for further diagnosis and treatment of KS.

MP43-06 TESTOSTERONE THERAPY IN MEN WITH KLINEFELTER SYNDROME: ANALYSIS OF A GLOBAL FEDERATED RESEARCH NETWORK

You have accessJournal of UrologyCME1 Apr 2023MP43-06 TESTOSTERONE THERAPY IN MEN WITH KLINEFELTER SYNDROME: ANALYSIS OF A GLOBAL FEDERATED RESEARCH NETWORK Katherine Campbell, Justin Loloi, Chase Carto, and Ranjith Ramasamy Katherine CampbellKatherine Campbell More articles by this author , Justin LoloiJustin Loloi More articles by this author , Chase CartoChase Carto More articles by this author , and Ranjith RamasamyRanjith Ramasamy More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003289.06AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Klinefelter Syndrome (KS, 47 XXY) represents the most common genetic form of male hypogonadism. Given the degree and prevalence of hypogonadism in these men, it is recommended that patients with KS and testosterone deficiency should be treated with lifelong testosterone supplementation (TRT) that begins at puberty to secure the development of sexual male characteristics and prevent long-term sequelae. Primary hypogonadism (including KS) is an on-label indication for TRT. The objective of this study was to determine the rates of hypogonadism and prescription of TRT in men with KS. We hypothesized that men with KS are under treated for testosterone deficiency with TRT because of the relationship between KS and neurocognitive impairment. METHODS: We queried TriNetX, a large, multicenter electronic health record database, to identify all men with a diagnosis of Klinefelter syndrome (ICD-10-CM Q98.4). We collected data on comorbidities including cognitive impairment, type 2 diabetes mellitus, obesity, hyperlipidemia, hypertension, osteoporosis in addition to demographic characteristics. Prevalence of testosterone deficiency was determined as defined by testosterone level <300 ng/dl. The primary outcome of the study was prescription of any of the following forms of TRT on the day of diagnosis or later. RESULTS: There were 5,437 total men with diagnosis of KS. A total of 1,581 men with KS received laboratory measurement of testosterone level, 1,113 (70.4%) of whom were hypogonadal. Mean testosterone level in this group was 354 ng/dL [50–658]. Of the 1,113 men found to be hypogonadal, only 657 (59.0%) men were given prescription for TRT. CONCLUSIONS: Despite the recent addition of KS as an indication for treatment to the FDA-approved label for TRT, in this large, retrospective study, TRT was under-prescribed in men with KS. Under treatment of hypogonadism in men with KS can lead to long-term consequences such as metabolic syndrome and cognitive impairment. This is the first study to evaluate TRT prescribing patterns in men with KS. Future research is needed to corroborate these findings and to evaluate barriers, especially as related to to receiving care in this population. Source of Funding: This work was supported by NIH Grant R01 DK130991 and Clinician Scientist Development Grant from the ACS to Ranjith Ramasamy © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e603 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Katherine Campbell More articles by this author Justin Loloi More articles by this author Chase Carto More articles by this author Ranjith Ramasamy More articles by this author Expand All Advertisement PDF downloadLoading ...

Testosterone Therapy in Men with Klinefelter Syndrome: Analysis of a Global Federated Research Network.

The objective of this study was to determine the rates of hypogonadism and prescription of testosterone replacement therapy (TRT) in men with Klinefelter syndrome (KS). We hypothesized that men with KS are under-treated for testosterone deficiency with TRT due to a combination of factors, including a poor understanding of hypogonadism in this population and neurocognitive issues leading to delay in seeking of treatment for hypogonadism. We queried TriNetX, a large multicenter electronic health record database, to identify all men with a diagnosis of KS (ICD-10-CM Q98.4). Prevalence of testosterone deficiency was determined as defined by testosterone level < 300 ng/dL. The primary outcome of the study was prescription of any of the following forms of TRT on the day of diagnosis or later. There were in total 5437 men with diagnosis of KS. A total of 1581 men with KS received laboratory measurement of testosterone level, 1113 (70.4%) of whom were hypogonadal. Mean testosterone level in this group was 354 ng/dL [50-658]. Of the 1113 men found to be hypogonadal, only 657 (59.0%) men were given prescription for TRT. This is the first study to evaluate TRT prescribing habits in men with KS. In this large retrospective study, TRT was underprescribed in men with KS. Further studies are needed to corroborate these findings and to evaluate barriers to receiving care in this population.

Clinical, cytogenetic, and genomic analyses of an Ecuadorian subject with Klinefelter syndrome, recessive hemophilia A, and 1;19 chromosomal translocation: a case report

BackgroundHemophilia A is considered one of the most common severe hereditary disorders. It is an X-linked recessive disease caused by a deficiency or lack of function of the blood clotting factor VIII. Klinefelter syndrome is a genetic disorder that affects male individuals due to one or more extra X chromosomes, present in all cells or with mosaicism. The aneuploidy is due to either mitotic or meiotic chromosome non-disjunction. Chromosomal translocations are a group of genome abnormalities in which a region or regions of a chromosome break and are transferred to a nonhomologous chromosome or a new location in the same chromosome.Case presentationOur subject was born in Ecuador at 36 weeks of gestation by vaginal delivery. At 3 months old, the Factor VIII activity measure showed a 23.7% activity indicating a diagnosis of mild hemophilia A. At 1 year old, the karyotype showed an extra X chromosome, consistent with a diagnosis of Klinefelter syndrome, and a translocation between the long arms of chromosomes 1 and 19, at positions q25 and q13, respectively.ConclusionsKlinefelter syndrome and hemophilia are a rare combination. In the present case report, the subject presents both, meaning that he has inherited one X chromosome from the father and one X chromosome from the mother. Since the father has severe hemophilia A; and the subject presents a below 40% Factor VIII activity, a skewed X inactivation is suggested. Additionally, the proband presents a translocation with the karyotype 47,XXY,t(1;19)(q25;q13). No similar report with phenotypic consequences of the translocation was found. The present report highlights the importance of a correct diagnosis, based not only on the clinical manifestations of a disease but also on its genetic aspects, identifying the value of integrated diagnostics. The subject presents three different genetic alterations, Klinefelter syndrome, hemophilia A, and a 1;19 chromosomal translocation.

PD36-04 AROMATIZATION OF ENDOGENOUS TESTOSTERONE OCCURS PRIMARILY IN TESTICULAR LEYDIG CELLS

You have accessJournal of UrologyCME1 May 2022PD36-04 AROMATIZATION OF ENDOGENOUS TESTOSTERONE OCCURS PRIMARILY IN TESTICULAR LEYDIG CELLS Caroline Kang, Nahid Punjani, Jessica Marinaro, and Peter Schlegel Caroline KangCaroline Kang More articles by this author , Nahid PunjaniNahid Punjani More articles by this author , Jessica MarinaroJessica Marinaro More articles by this author , and Peter SchlegelPeter Schlegel More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002594.04AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Endogenous testosterone (T) is produced by testicular Leydig cells that are rich in aromatase activity. Aromatization to estradiol (E2) can negatively regulate the hypothalamic-pituitary-testis (HPT) axis, thereby diminishing gonadotropin and T production as well as spermatogenesis. Exogenous T is exposed primarily to fat, muscle, and other peripheral tissues with limited exposure to testicular Leydig cells. We investigated the source of aromatization by comparing serum T:E2 ratios, as a surrogate for aromatase activity, in men with Klinefelter syndrome (KS) who have endogenous or exogenous testosterone production, that is, before and after the initiation of testosterone replacement therapy (TRT). METHODS: We performed a retrospective study of all adult men (> 20 years of age) with a diagnosis of KS undergoing sperm retrieval by microdissection testicular sperm extraction (mTESE) performed by a single surgeon at a tertiary infertility referral center between 1995-2020. Demographic data, along with hormone data (serum T and E2 levels) pre- and post-TRT were obtained from the electronic medical record. Patients not treated with TRT or with incomplete hormone data were excluded. Paired statistical analyses were completed to determine differences between hormone levels pre- and post-TRT initiation. RESULTS: A total of 35 men with KS were included in our final analysis. Median age was 32 years (interquartile range (IQR), 28 - 36), and median BMI was 25.9 kg/m2 (IQR, 24.6 - 30.8). The majority of our cohort was initiated on topical TRT (e.g., cream or gel; 26/35, 74.3%), while the remaining were treated with injectable or implanted TRT (9/35, 25.7%). Mean serum T increased from 239±134 ng/dL to 519±361 ng/dL (p=0.0003), while mean serum E2 increased from 30±22 pg/ml to 36±28 pg/ml (p=0.55) after initiation of TRT. Mean T:E2 ratio increased from 9.4±6.3 to 17.4±14.5 (p=0.0005) after initiation of TRT. CONCLUSIONS: Aromatization of T to E2 can result in suppression of the HPT axis and diminish both T production and spermatogenesis. After initiation of TRT, T:E2 ratios rose significantly due to an increase in T with relatively stable E2, suggesting that exogenous and endogenous T are not subject to the same cellular milieu and therefore differential aromatization. This finding has important implications in the treatment and counseling of men with infertility and abnormal hormone levels. Source of Funding: CK and JS are supported in part by the Frederick J. and Theresa Dow Wallace Fund of the New York Community Trust © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e634 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Caroline Kang More articles by this author Nahid Punjani More articles by this author Jessica Marinaro More articles by this author Peter Schlegel More articles by this author Expand All Advertisement PDF DownloadLoading ...

Communicating the diagnosis of Klinefelter syndrome to children and adolescents: when, how, and who?

Klinefelter syndrome (KS) is the most frequent sex chromosome aneuploidy in males. KS diagnosis disclosure has an important impact on diagnosis acceptance and the increase in prenatal diagnostic procedures raises questions regarding communication to children/adolescents. Limited data are currently available on this issue. The aim of the study was to investigate aspects like the best timing (when), topics (how), and healthcare professional (who), which, in the opinion of both KS patients and parents, may be considered the best for diagnosis communication to KS children/adolescents. We also analyzed how participants received the communication in real life and evaluated the differences between the responses given by parents who receive KS diagnosis before or after KS patient birth regarding disclosure of KS communication. KS adult patients, KS mothers, and KS fathers, not belonging to the same family, completed a questionnaire containing quantitative measures (5 points Likert scale), open-ended questions, and multiple choice questions. Parental responses were divided according to the timing at which the communication occurred: prenatal age diagnosis (PRE-D) or postnatal age diagnosis (POST-D). A total of 41 KS adults and 77 KS parents (53 PRE-D, 24 POST-D) were recruited. Most KS patients and most POST-D parents consider that communication should be provided before 14 years of age; most PRE-D parents consider 14–18 years of age the best period for communication. We suggest that communication should occur preferably before 18 years of age by a multidisciplinary team (endocrinologists, psychologists, geneticists, and parents) and that the information should deal not only fertility and hormonal aspects but also metabolic and cognitive features.

Lipedema and Klinefelter Syndrome in Two Morbidly Obese Patients

Introduction: Lipedema is an abnormal deposit of subcutaneous fat most often involving the lower limbs symmetrically. The physiopathology is poorly understood, but its peak of the almost exclusively female involvement and its peak of appearance at puberty, during pregnancy or at menopause orient toward a hormonal involvement, whereas other elements are in favor of a strong genetic predisposition. Klinefelter syndrome (KS) is a genetic disease linked to aneuploidy resulting in a karyotype 47 XXY most of the time. There is a substantial variation in clinical presentation, but it often features infertility, firm testicular hypotrophy, hypergonadotropic hypogonadism, gynecomastia, and learning difficulties. Many other pathologies are associated with KS, but lipedema is never mentioned and there are no data in the literature linking these two pathologies. Observation: We report the cases of a 55-year-old man (146.8 kg, body mass index [BMI] 40.96 kg/m2) whose diagnosis of KS was known when hospitalized for lipedema, and of a 62-year-old man (198.1 kg, BMI 68.55 kg/m2) whose diagnosis of KS was made after the hospitalization for lipedema. Discussion: The concomitant presence of these two rare pathologies encourages the construction of an epidemiological study to support this association. It is also an element that can feed the research on the physiopathology of these two affections. Finally, the clinician must know how to suspect the possibility of lipedema in a patient with KS presenting an enlargement of the lower limbs and should know how to evoke a diagnosis of KS in front of a lipedema aspect in a man.

952 Prenatal phenotype of 47,XXY (Klinefelter syndrome)

The phenotypic description of prenatal Klinefelter syndrome (KS), or 47,XXY, is currently limited to case reports. There is a gap in knowledge regarding prenatal presentation of KS. We hypothesize that a significant percentage of pregnancies complicated by fetal KS will have associated ultrasonographic findings. We retrospectively identified all fetuses with cytogenetically confirmed 47,XXY in the prenatal period or up to age 5 years, with prenatal records available for review from four prenatal diagnostic referral centers between 2006 and 2019. Ultrasound reports were reviewed to assess for the presence of increased nuchal translucency (NT) and abnormalities at the second trimester anatomy ultrasound. Additionally, we reviewed results of cell free DNA and serum analyte testing to inform our understanding of prenatal screening tests in the setting of fetal KS. A total of 42 subjects with confirmed cytogenetic diagnosis of 47,XXY and prenatal records available for review were identified: 38 had a prenatal diagnosis of KS and 4 had a postnatal diagnosis. One case was excluded as cytogenetic analysis demonstrated mosaic KS, leaving a cohort of 41 subjects. NT was increased ≥3.0mm in 6 of 26 (23.1%) of cases that had a documented measurement. A second trimester anatomical survey was available for review in 24/41 affected pregnancies. In 7 of 24 (29.2%) ultrasounds, a fetal abnormality was identified. These include 3 brain anomalies, 1 cardiac abnormality, 1 echogenic bowel, and 2 limb abnormalities (table). In subjects who had cell free DNA performed, 92.6% had a positive result for 47,XXY (25/27); in subjects who had serum analytes performed, 36.3% (4/11) had a positive result. This case series expands our knowledge of the prenatal presentation of KS by identifying 1st and 2nd trimester fetal sonographic abnormalities as well as serum analyte abnormalities.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Idiopathic central precocious puberty in a Klinefelter patient: highlights on gonadotropin levels and pathophysiology

BackgroundIdiopathic central precocious puberty (ICPP) is supposed to be non-existent in a context of testicular destruction that is typically present in Klinefelter syndrome (KS). Herein, we describe a rare case of ICPP in a Klinefelter patient (47,XXY) with 2 maternal X chromosomes. Moreover, we highlight the differences in gonadotropin levels in comparison to males with ICPP and a normal karyotype.Case presentationAn 8 years old boy with a history of cryptorchidism was evaluated for precocious puberty (Tanner staging: P2/G3). Both testes measured 25x35mm. His hormonal profile confirmed a central origin of precocious puberty with high serum testosterone (4.3 ng/ml), luteinizing hormone [LH (3.5 UI/l)] and follicle stimulating hormone [FSH (7.7 UI/l)] levels. Luteinizing hormone-releasing hormone (LHRH) test amplified LH and FSH secretion to 24 and 14 UI/l respectively. Brain magnetic resonance imaging (MRI) was normal. No MKRN3 mutation was detected. He was treated for ICPP for two years. During puberty, he suffered from hypergonadotropic hypogonadism leading to the diagnosis of KS (47,XXY karyotype). Chromosomal analysis by fluorescent multiplex polymerase chain reaction (PCR) using X chromosome microsatellite markers identified 2 maternal X chromosomes.Analysing 8 cases of KS developing ICPP (our reported case and 7 other published cases) revealed that these KS patients with ICPP have higher LH and FSH levels during ICPP episode than in ICPP patients with a normal karyotype (ICPP with KS vs ICPP with a normal karyotype: LH levels 9.4 ± 12 vs 1.1 ± 0.6 UI/l; FSH levels 23.1 ± 38.5 vs 2.7 ± 1.5 UI/l). Furthermore, their response to gonadotropin-releasing hormone (GnRH) stimulation is characterized by excessive LH and FSH secretion (LH levels post-GnRH: 58 ± 48 vs 15.5 ± 0.8 UI/l; FSH levels post-GnRH: 49.1 ± 62.1 vs 5.7 ± 3.9 UI/l).ConclusionsICPP in boys is extremely rare. The pathophysiology of ICPP in KS is unknown. However, maternal X supplementary chromosome and early testicular destruction may play a significant role in the initiation of ICPP, in part explaining the relative “overrepresentation of ICPP in KS. Thus, karyotype analysis could be considered for boys suffering from ICPP, especially if testicular size is smaller or gonadotropins are significantly elevated.

Prevalence and determinants of radiological vertebral fractures in patients with Klinefelter syndrome.

Klinefelter syndrome (KS) may induce skeletal fragility, but the studies so far published on this topic were mainly focused on the evaluation of bone mineral density (BMD) and bone microstructure, whereas data on fracture risk are still lacking. To evaluate the prevalence and determinants of vertebral fractures (VFs), that is, the hallmark of osteoporosis, in subjects with KS. Eighty-seven patients with KS (median age 41years, range 18-64) were consecutively evaluated for radiological VFs (by quantitative morphometry) and lumbar spine and femoral neck BMD (by DXA). Fifty-five patients with KS were also evaluated by the fracture risk assessment (FRAX) tool. Low BMD was found in 22/87 (25.3%) patients [12 with osteopenia, three with osteoporosis and seven with "low BMD per age" (subject<50years with Z-score ≤-2.0 SD)] and VFs in 13/87 (14.9%) patients. In patients with VFs, the median spine deformity index was 2 (range 1-9). Prevalence of VFs was similar between healthy and low-BMD patients (15.9% vs 13.6%; P=.80). Noteworthy, patients with VFs had significantly higher age at diagnosis of KS as compared to patients who did not fracture (P=.039), without significant differences in age at the time of observation (P=.162), body mass index (P=.234), testosterone replacement therapy (P=.432), duration of testosterone therapy (P=.409), vitamin D therapy (P=681), and serum testosterone levels (P=.338). Moreover, patients with VFs were more likely to complain back pain in comparison with those without VFs (33.3% vs 7.4%; P=.047). In 55 cases evaluated by the FRAX®tool, no significant differences in 10-year risk of major fracture (P=.270) and hip fracture (P=.860) were found between fractured and non-fractured patients. This study provides first evidence that KS may be associated with risk of VFs in close relationship with delay in disease diagnosis but independently of BMD values and serum testosterone levels or testosterone therapy.

MON-254 Sympromic Hypogonadism: Co- Existence of Morsier and Klinefelter Syndromes

INTRODUCTION: Morsier Syndrome is a rare congenital malformation, characterized by hypoplasia / aplasia of the septum pellucidum and hypoplasia / aplasia of the optic nerves, in addition to pituitary and hypothalamic hormonal deficiencies. Klinefelter Syndrome is a sexual chromosomal genetic alteration, a frequent cause of male hypogonadism, The association of Morsier syndrome and Klinefelter is described below.CLINICAL CASEWe report he case of a 12 year-old boy with psychomotor retardation and nystagumsho presented at 14 months of age with growth hormone deficiency (low weight and height,) and diabetes insipuidus with hypernatremia of of 159 mEq and low urinary density (less than 1,005).MRI showed an absence of septum pellucidum, thick right frontal cortical dysplasia with asymmetric appearance of the grooves, small optic chiasma, hypoplastic pitutary gland (3 mm height), compatible with Morsier syndrome.The physical examination draws attention to tall stature, and long lower limbs, facies with prominent forehead and hypertelorism, gynecomastia and small external genitalia for age.Hormonal evaluation revealed hypergonadotropic hypogonadism with a 47 XXY karyoteype suggeting Klinefelter syndrome.CONCLUSION:We report the first case of Morsier syndrome, associated to Klinefelter syndrome. Both syndromes may present with hypogonadism. However, the diagnosis of klinefelter syndrome was made based on the phenotypic characteristics of this patient including hyeprgonadotroic hypogonadism and abnormal karyotype analysis.

Perspectives of adults with Klinefelter syndrome, unaffected adolescent males, and parents of affected children toward diagnosis disclosure: a Thai experience

Little is known about disclosure of diagnosis to males with Klinefelter syndrome (KS) diagnosed before birth or during childhood, especially in Asian context. Insufficient preparation for disclosure communication could lead to the child’s depression, anxiety, or disrupted self-esteem. This is an interventional and qualitative interview study with a brief self-reported survey. The study consists of three phases. In phase I, adults with KS were asked about their experiences and viewpoints toward KS disclosure and diagnosis through individual interviews. In phase II, unaffected adolescent males were given information about KS and then asked to give hypothetical answers to a questionnaire followed by a group interview, as if they had KS. In phase III, parents of children with KS were asked to complete a questionnaire followed by a group interview which included a discussion about their disclosure plans and their concerns. The parents were provided information obtained from adults with KS and unaffected adolescent males, and were then interviewed again as a group. We found that the most hurtful issues were discovering their infertility from KS and late disclosure. From the perspective of unaffected adolescent males, early disclosure in early or mid-teens in a neutral, supportive, and relaxed manner, along with information on benefits of hormonal treatment, the assurance of biological sex as “male,” and avoidance of some sensitive words are strongly recommended, as a way to promote self-confidence and positive coping with the diagnosis. After intervention, the parents reported more confidence and less anxiety about disclosing the diagnosis to their children, and indicated that they would disclose KS at an earlier age. For unaffected adolescent males, though it is a hypothetical scenario and their reaction may differ from affected adolescents, unaffected adolescent males’ viewpoints on how they might react are more or less representative of cultural changes for the new generation, especially in the Asian context. In addition, their viewpoints influenced parents’ decision and genetic counseling plans for the diagnosis disclosure of KS to their children. We propose a preliminary guideline for KS diagnosis disclosure.

Spojenie akromegálie a Klinefelterovho syndrómu u jedného pacienta

Acromegaly is a rare disorder usually caused by a benign tumour of the pituitary gland. Long-term presence of elevated growth hormone (GH) and insulin like growth factor 1 (IGF1) levels accompanying this disease is associated with complications such as cardiomyopathy, diabetes mellitus, sleep apnoea and arthropathy. Incidence of acromegaly is 3-4 patients per million per year. Klinefelter syndrome (KS) is the most common sex chromosome disorder occuring in about 1/500 live male births. Common physical features include particularly small testes, among other symptoms are tall stature, reduced muscle tone, delayed pubertal development, lack of secondary male sex characteristics and gynecomastia. We present a 32-year-old man suffering from both acromegaly and 47, XXY Klinefelter syndrome. The patient with typical acromegalic features. Laboratory tests revealed high level of GH which was not suppressed after glucose administration, high level of IGF1, low testosterone concentration with high concentation of luteinizing hormone and follicle stimulating hormone. A magnetic resonance imaging scan revealed a 25 × 18 × 18 mm macroadenoma involving the pituitary gland. A diagnosis of acromegaly was established. After this examination trans-sphenoidal resection was performed. Histopathologic and immunohistochemical findings revealed growth hormoneproducing pituitary adenoma. The presence of infertility with clinical features such as small testes, lack of secondary male sex characteristics and laboratory findings revealed hypergonadotropic hypogonadism that could not be explained by the diagnosis of acromegaly. A chromosomal karyotyping revealed a 47, XXY, confirming the diagnosis of KS. Testosterone replacement therapy wasn´t begun because of patient disagreement Postoperatively elevated plasma concentration of GH and IGF1 levels persist. Treatment by somatostatin analogues (lanreotid) was initiated at dose 120 mg every 28 days. Control magnetic resonance imaging of the sella demonstrated a residue of pituary adenoma size 14 × 14 × 7 mm. The patient is currently undergoing endoscopic revision of the residue. acromegaly - growth hormone - IGF1 - Klinefelter syndrome - testosterone.

Klinefelter syndrome in males with germ cell tumors: A report from the Children's Oncology Group.

Males with Klinefelter syndrome (KS) (47,XXY) may be more likely to develop germ cell tumors (GCTs), particularly mediastinal GCTs. To date, there are no reports characterizing the prevalence of KS among male GCT cases. The authors used array genotyping data from a Children's Oncology Group epidemiology study to estimate the prevalence of KS in males with GCTs (433 males aged birth-19 years). Using Fisher's exact tests, the authors examined differences in age at diagnosis, race/ethnicity, tumor location and histology, and several birth characteristics between cases of KS-GCT and GCT cases without chromosomal abnormalities. Using publicly available data, the authors estimated the 1-year risk, risk ratio, and corresponding 95% confidence interval of GCTs among KS cases. Based on analysis of array genotyping data, 3% of male GCT cases (13 cases) had KS. The additional X chromosome was of maternal origin in 7 of the 13 cases. Of these 13 KS cases, 5 of 9 KS-GCT cases with parental questionnaire data (56%) reported a diagnosis of KS. No significant differences were observed with regard to patient or birth characteristics between KS-GCT and non-KS-GCT cases. KS-GCT cases were significantly more likely to be diagnosed with mediastinal tumors than non-KS-GCT cases (P<.01). The authors estimated the risk of developing a GCT among males with KS to be 0.00025, or 1 per 4000 males (risk ratio, 18.8; 95% confidence interval, 11.7-30.0). Compared with males without chromosomal abnormalities, males with KS are more likely to be diagnosed with a mediastinal GCT. The presence of KS should be considered in males with a diagnosis of mediastinal GCT. In the current study, the authors report that approximately one-third of males with mediastinal germ cell tumors have Klinefelter syndrome, and therefore screening of these individuals for the syndrome may be warranted. Males with Klinefelter syndrome are 19 times as likely as males without Klinefelter syndrome to develop germ cell tumors.

An Analysis of Cytogenetic and Clinical Phenotype of Klinefelter Syndrome Over 17 Years

Background: Clinical phenotype in Klinefelter syndrome (KS) shows utmost contrariety according to the genetic presentation. The karyotype 47, XXY is one of the commonest types of sex chromosomal abnormality in males presenting with infertility, hypogonadism, small penis, gynaecomastia and tall stature. Cytogenetic study is the only way to differentiate between chromosomal abnormality and other androgen deficiency disorders. The aim of this study was to investigate cytogenetic and phenotypic profile of Klinefelter syndrome in a group of referred patients with suspected genetic disorders.Methods: This observational study was carried out at the Cytogenetic Laboratory of the Department of Immunology BIRDEM General Hospital for a period of seventeen years from 2000 to 2016. A total of 9,216 patients suspected for different chromosomal abnormalities (e.g. numerical chromosomal disorders, primary amenorrhoea, ambiguous genitalia etc.) were included in this study referred by physicians of various discipline from different areas of Bangladesh. From the patients referred for cytogenetic study, detailed family history and physical findings were noted. Complete genetic examination and pedigree construction was done to exclude non-chromosomal causes of anomalies. For cytogenetic analysis, peripheral lymphocyte culture by the standard method using the G-banding technique was employed.Results: In this study 1.67% (154) of referred patients were diagnosed as Klinefelter syndrome in cytogenetic study and most of them were diagnosed in their adulthood between 20-29 years of age. Classical cytogenetic form of KS-47, XXY (87%) were most common followed by other mosaic and supernumerary X chromosome aneuploidy. Most of the patients presented with tall stature (61.7%) followed by other features such as gynaecomastia (45.5%), eunuchoid skeleton (29.8%), sexual dysfunction (34.41%), small penis (22.7%), and delayed development of secondary sex characteristics (22.7%).Conclusion: Diagnosis of Klinefelter syndrome in early age before puberty is needed to be differentiated from other related disorders and thereby improving the quality of life by providing appropriate and timely treatment. Therefore, we have to focus to improve our overall capacity to diagnose genetic disorders for proper interventionBirdem Med J 2018; 8(2): 126-131

Fertility Preservation in Klinefelter Syndrome Patients during the Transition Period.

Spermatozoa have occasionally been identified in ejaculate of adult Klinefelter syndrome (KS) patients but very exceptionally in KS adolescents. Spermatozoa can also be retrieved in testicular tissue of KS adolescents. The testis may also harbor spermatogonia and noncompletely differentiated germ cells. Neither clinical features nor hormonal parameters could predict germ cell recovery in KS adults or adolescents. No predictive factors can actually demonstrate that early diagnosis of KS would allow increasing the chance of sperm retrieval even if it has been suggested that semen quality may decline with age in KS patients. Leydig cell dysfunction may also be another factor that might affect the spermatogenesis process in XXY adolescents. Fertility preservation might be preferentially proposed in KS adolescents when semen sampling is possible, when the patient is able to consider alternative options to become a father, and to accept germ cell retrieval failure. However, precocious diagnosis of KS has also to be considered because it might not solely improve the possibility of fertility preservation after the onset of puberty, but also the medical care and the quality of life of these patients.