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Spermatogenesis involves the aggregated action of up to 2300 genes, any of which, could, potentially, provide targets for diagnostic tests of male factor infertility. Contrary to the previously proposed common variant hypothesis for common diseases such as male infertility, genome-wide association studies and targeted gene sequencing in cohorts of infertile men have identified only a few gene polymorphisms that are associated with male infertility. Unfortunately, the search for genetic variants associated with male infertility is further hampered by the lack of viable animal models of human spermatogenesis, difficulty in robustly phenotyping infertile men and the complexity of pedigree studies in male factor infertility. In this review, we describe basic genetic principles involved in understanding the genetic basis of male infertility and examine the utility and proper clinical use of the proven genetic assays of male factor infertility, specifically Y chromosome microdeletions, chromosomal translocations, karyotype, cystic fibrosis transmembrane conductance regulator mutation analysis and sperm genetic tests. Unfortunately, these tests are only able to diagnose the cause of about 20% of male factor infertility. The remainder of the review will be devoted to examining novel tests and diagnostic tools that have the potential to explain the other 80% of male factor infertility that is currently classified as idiopathic. Those tests include epigenetic analysis of the spermatozoa and the evaluation of rare genetic variants and copy number variations in patients. Success in advancing to the implementation of such areas is not only dependent on technological advances in the laboratory, but also improved phenotyping in the clinic., (© 2014 American Society of Andrology and European Academy of Andrology.)

49, XXXXY syndrome is a rare sex chromosome aneuploidy occurring in 1:80 000-1:100 000 male births. Data on this aneuploidy in adulthood are limited, with most of the literature data based on paediatric patients. We report a new male patient whose 49, XXXXY diagnosis was formally made at the age of 54 years. So far, no medical follow-up was performed specifically for his condition. This man presented with facial features (epicanthus, hypertelorism, up-slanting palpebral fissures), microorchidism and features of chronic hypoandrogenism with muscular weakness, sparse body hair, dry skin with abnormal healing of skin wounds. Endocrine evaluation confirmed a hypergonadotropic hypogonadism. He had moderate intellectual deficiency with more affected verbal skills. A recent deep vein thrombosis was diagnosed in his left leg. Unusually, in addition to moderate deafness, he developed progressively a severe vision impairment leading to blindness. There have been very few reports of adult individuals with 49, XXXXY syndrome and this kind of report may contribute to improved management of prospective medical healthcare associated with this condition in older individuals.

Male infertility, affecting around half of the couples with a problem to get pregnant, is a very heterogeneous condition. Part of patients are having a defect in spermatogenesis of which the underlying causes (including genetic ones) remain largely unknown. The only genetic tests routinely used in the diagnosis of male infertility are the analyses for the presence of Yq microdeletions and/or chromosomal abnormalities. Various other single gene or polygenic defects have been proposed to be involved in male fertility. Yet, their causative effect often remains to be proven. The recent evolution in the development of whole genome-based techniques may help in clarifying the role of genes and other genetic factors involved in spermatogenesis and spermatogenesis defects., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

Objective: To determine whether men with Klinefelter syndrome (KS) have the same phenotype as men with mosaic KS., Design: Subject identification via prospectively collected database., Setting: Male infertility specialty clinic., Patient(s): Men undergoing a fertility evaluation from 2005 to 2012 at a single male infertility specialty clinic and having a karyotype demonstrating KS (mosaic or non-mosaic)., Intervention(s): None., Main Outcome Measure(s): Testicular size, and semen and hormone parameters, genetic evaluation, and signs of testosterone (T) deficiency using validated questionnaires., Result(s): Of 86 men identified with KS, 6 (6.7%) were mosaic KS, and 80 (93.3%) were non-mosaic KS. Men with mosaic KS had lower baseline luteinizing hormone (LH) levels (10.31 IU/L ± 5.52 vs. 19.89 IU/L ± 6.93), lower estradiol levels (58.71 ± 31.10 pmol/L vs. 108.57 ± 43.45 pmol/L), larger mean testicular volumes (11 ± 7.3 mL vs. 6.35 ± 3.69 mL), and a higher mean total sperm count (4.43 ± 9.86 M/mL vs. 0.18 ± 1.17 M/mL). A higher proportion of men with mosaic KS had sperm in the ejaculate: 3 (50%) of 6 versus 3 (3.75%) of 80. The Sexual Health Inventory for Men (SHIM) and Androgen Deficiency in the Aging Male (ADAM) questionnaire scores were not different between groups., Conclusion(s): Men with mosaic KS seem to be more well androgenized than their non-mosaic KS counterparts, both with respect to hormones and sperm in the ejaculate., (Copyright © 2014 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Studies of sex effects on neurodevelopment have traditionally focused on animal models investigating hormonal influences on brain anatomy. However, more recent evidence suggests that sex chromosomes may also have direct upstream effects that act independently of hormones. Sex chromosome aneuploidies provide ideal models to examine this framework in humans, including Turner syndrome (TS), where females are missing one X-chromosome (45X), and Klinefelter syndrome (KS), where males have an additional X-chromosome (47XXY). As these disorders essentially represent copy number variants of the sex chromosomes, investigation of brain structure across these disorders allows us to determine whether sex chromosome gene dosage effects exist. We used voxel-based morphometry to investigate this hypothesis in a large sample of children in early puberty, to compare regional gray matter volumes among individuals with one (45X), two (typically developing 46XX females and 46XY males), and three (47XXY) sex chromosomes. Between-group contrasts of TS and KS groups relative to respective sex-matched controls demonstrated highly convergent patterns of volumetric differences with the presence of an additional sex chromosome being associated with relatively decreased parieto-occipital gray matter volume and relatively increased temporo-insular gray matter volumes. Furthermore, z-score map comparisons between TS and KS cohorts also suggested that this effect occurs in a linear dose-dependent fashion. We infer that sex chromosome gene expression directly influences brain structure in children during early stages of puberty, extending our understanding of genotype-phenotype mechanisms underlying sex differences in the brain.

Sex chromosome aneuploidies are a common group of disorders that are characterised by an abnormal number of X or Y chromosomes. However, many individuals with these disorders are not diagnosed, despite established groups of core features that include aberrant brain development and function. Clinical presentations often include characteristic profiles of intellectual ability, motor impairments, and rates of neurological and psychiatric disorders that are higher than those of the general population. Advances in genetics and neuroimaging have substantially expanded knowledge of potential mechanisms that underlie these phenotypes, including a putative dose effect of sex chromosome genes on neuroanatomical structures and cognitive abilities. Continuing attention to emerging trends in research of sex chromosome aneuploidies is important for clinicians because it informs appropriate management of these common genetic disorders. Furthermore, improved understanding of underlying neurobiological processes has much potential to elucidate sex-related factors associated with neurological and psychiatric disease in general., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: Previous case series suggested a link between Klinefelter syndrome (KS) and essential tremor (ET) or an ET-like syndrome., Methods: We investigated three KS-patients with tremor including tremor-analyzes and discuss our data in context to findings from a literature review. The clinical outcome after deep brain stimulation (DBS) is also reviewed., Results: Tremor in KS is predominantly a postural and kinetic tremor that resembles ET. Our patients were further characterized by absent family history for tremor in first degree relatives, lack of subjective alcohol responsiveness inquired by history, and tremor onset in childhood. One of our patients and two cases from literature improved after DBS of the ventral intermediate nucleus (VIM) of the thalamus., Conclusions: Tremor in KS shares several features with ET. If other characteristics such as family history, alcohol responsiveness, and age at tremor onset may serve as discriminating factors from ET, needs to be further investigated. First observations suggest that VIM-DBS may be efficacious., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Hypogonadism is defined as defects in gonadal response to gonadotropins or sex hormone biosynthesis. Clinical evaluation and diagnosis of patients is challenging, particularly before puberty. Basal determinations of the gonadotropins luteinizing hormone, follicle-stimulating hormone, the gonadal sex steroids testosterone and/or estrogen and markers of gonadal function including inhibin B and anti-Müllerian hormone are useful, but only at specific ages, thus necessitating combined hormonal tests with meticulous physical examination. GnRH testing can be useful, and may be used in combination with hCG testing to discriminate between isolated hypogonadotropic hypogonadism and constitutional delay of growth and puberty. Urine steroid profiles may be helpful in the diagnosis of androgen biosynthetic defects. Also increasingly important is genotypic screening for genetic or chromosomal abnormalities, together with detailed family and medical histories including antecedent substance abuse, chronic disease, and exposure to chemotherapy or radiotherapy. This chapter explores the diagnosis and evaluation of patients with hypogonadism and reviews the genetic/chromosomal factors involved in the condition.

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.

The present study aimed to gain more insight in the social behavioral phenotype, and related autistic symptomatology, of children with an extra X chromosome in comparison to children with ASD. Participants included 60 children with an extra X chromosome (34 boys with Klinefelter syndrome and 26 girls with Trisomy X), 58 children with ASD and 106 controls, aged 9 to 18 years. We used the Autism Diagnostic Interview, Social Responsiveness Scale, Social Anxiety Scale and Social Skills Rating System. In the extra X group, levels of social dysfunction and autism symptoms were increased, being in between controls and ASD. In contrast to the ASD group, the extra X group showed increased social anxiety. The effects were similar for boys and girls with an extra X chromosome.

We report a seven-year-old boy with 48,XXYY karyotype, presenting with tremor and a slight retardation of psychomotor development. Although the physical phenotype is similar to 47,XXY, 48,XXYY is associated with additional medical problems and more significant neurodevelopmental and psychological features. Increased awareness of such features is important to facilitate timely diagnosis and initiation of appropriate screenings and treatments. Karyotyping should be considered in individuals presenting with tremor and a history of develop-mental delay, learning disabilities, tall stature or micro-orchidism.

Background: Klinefelter syndrome (KS) is a common genetic condition affecting one in 450 men, but is only diagnosed in fewer than half of those affected., Objective: To increase awareness among general practitioners of their role in the diagnosis and management of KS., Discussion: KS has a highly varied phenotype comprising a range of physical and psychosocial features and comorbidities. For patients diagnosed with KS, a range of management strategies can be used to improve health outcomes and quality of life.

We report on a patient with a 47,XXY karyotype who presents a normal female phenotype, which is an extremely rare observation worldwide. The patient is infertile. Type B ultrasound scans and other tests suggested that her ovaries had completely failed. Microsatellite DNA marker analysis revealed that the 2 X chromosomes were derived from her mother and that this abnormality was caused by non-disjunction of the maternal X chromosomes during meiosis II. Copy number variation analysis identified 2 large de novo deletions in her Y chromosome. Remarkably, one of the deleted regions includes the SRY gene locus, which might explain her female phenotype. However, the genetic mechanism of her ovarian failure remains unclear. This paper is the first report of a 47,XXY female with ovarian failure., (© 2014 S. Karger AG, Basel.)

Klinefelter syndrome (KS) is a common genetic condition that is currently under-diagnosed. The phenotype is broad, with physical, medical and psychosocial features ranging from mild to severe. When a child is diagnosed with KS, the parents may spend months to years searching for a diagnosis. This study used a qualitative methods approach to explore parents' experiences of having a child with KS and receiving a diagnosis. Fifteen semistructured one-to-one in-depth interviews were conducted to explore their experiences and views. The interviews were then transcribed, coded and thematically analysed. The interviews revealed that parents had diverse experiences related to: the timing of the diagnosis of their child and reasons why their child was investigated for KS; the information that was provided at the time of diagnosis; the supports that were available and the concerns that parents held for the future of their child. The conclusions from this study were that parents' experiences of having a child with KS and receiving a diagnosis were complex and multifaceted. This experience was shaped by the timing of when the diagnosis was received, who provided the diagnosis, what information was provided from health-care professionals and that which parents may have encountered on the internet. The long-term experiences for parents were also impacted by the level of support they received. These findings have implications for the process by which KS is recognised by the health-care community and supports available for families.

Purpose: 48,XXYY syndrome was first described in 1964 and approximately 100 cases have been reported in the literature. We report a case of 48,XXYY syndrome associated with high myopia and retinal dysfunction., Methods: Case report., Results: A 28-year-old man was referred with progressive deterioration of visual acuity (VA) bilaterally during the previous 4-5 years. Physical examination revealed tall stature, large feet and irregular teeth. Refraction revealed high myopia with VA 6/60 bilaterally. Fundoscopy revealed a normal vitreous, lightly pigmented retinal pigment epithelium and choroid but no bone spicules or overt signs of retinal degeneration. His visual fields were constricted. Electrodiagnostic testing revealed bilateral generalised retinal dysfunction with severe macular involvement. During follow-up, his ophthalmic examination did not exhibit significant changes while VA was gradually deteriorating. Eight years after presentation, VA was 3/60 bilaterally; electrophysiological testing showed no further change. At that stage, his parents consented for DNA analysis in order to determine the cause of retinal dysfunction. Chromosomal analysis revealed an abnormal male karyotype with two X chromosomes and two Y chromosomes consistent with 48,XXYY syndrome., Conclusions: The present report is the first to describe retinal dysfunction and high myopia with 48,XXYY syndrome. The severe macular and generalised retinal dysfunction in this case are not those associated with myopia and are in keeping with a primary retinal dysfunction. A coincidental finding cannot be excluded, but ERGs have not previously been reported in 48,XXYY syndrome, and retinal dystrophy may be a previously undiagnosed component of this syndrome.

Gonosomal trisomies (GT) or so called sex chromosome trisomies (SCTs) are the most common chromosomal abnormalities in humans. The addition of extra X and/or Y chromosomes leads to neurodevelopmental differences, with increased risk for developmental delays, cognitive impairments, executive dysfunction, and behavioural and psychological disorders. Attentional problems, hyperactivity, autistic spectrum disorders and impulsivity are commonly described. Rates of language and communication problems are high in all 3 trisomies. Especially in cases of language impairment ENT specialists may be the main contact to rule out hearing loss. Here, we present 5 patients with SCT. In 2 boys and a young man, SCT was already known (47,XXY; 47,XYY; 47,XYY), in 2 cases we initiated genetic investigation (47,XXX; 47,XXY). Main symptom of the 4 children was a language delay; the young man reported had a history of mild language and motor coordination delay, too. Main complaints of the adult patient were problems with speech-in-noise perception. Furthermore 2 of the patients had mild facial dysmorphic features. The prognosis of the development in patients with SCT is variable, depending on severity of the manifestations and on quality and timing of treatment. Furthermore, in children with motor development/language delay a chromosomal analysis may be initiated at least at the request of the parents to clarify the etiology of developmental abnormalities. If the suspicion of hearing impairment as the cause of problems is not confirmed in a patient, ENT specialists should also consider SCA as a possible cause in the differential diagnosis., (© Georg Thieme Verlag KG Stuttgart · New York.)

Objective: To evaluate surgical sperm retrieval rates in adolescents with Klinefelter syndrome and testosterone replacement therapy (TRT)., Design: Case series., Setting: Academic medical center., Patient(s): Ten patients with Klinefelter syndrome, aged 14-22 years, treated with testosterone replacement and aromatase inhibitor therapy for a period of 1-5 years before surgical sperm retrieval., Intervention(s): Microsurgical testis sperm extraction with cryopreservation of harvested tissue., Main Outcome Measure(s): Presence of spermatozoa within testis tissue., Result(s): Successful sperm retrieval in 7/10 patients (70%)., Conclusion(s): Use of topical TRT did not appear to suppress spermatogenesis in adolescents with KS. It is uncertain whether sperm retrieval rates would be higher or lower without testosterone replacement in these young males. Sperm cryopreservation should be discussed in all KS adolescents who are either receiving or considering initiating TRT., (Copyright © 2013 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Klinefelter syndrome is a common condition that remains underdiagnosed, particularly prior to adulthood. Early detection could prevent morbidity and mortality, but the classic phenotype of small testes and tall stature may not be apparent until adolescence, and there is minimal guidance regarding whom to screen. We performed a retrospective study at Boston Children's Hospital in patients with the ICD-9 code for "Klinefelter syndrome" diagnosed prior to age 20 years, and determined age and reason for diagnosis, karyotype, heights, and comorbid conditions. Eighty percent had a 47,XXY karyotype, of whom half were diagnosed at age 11 to 19 years. The most common comorbidities were neurocognitive, including learning disabilities (67%), psychosocial problems (33%), and attention deficit disorder (27%). Subjects were only slightly taller than average in childhood (height standard deviation score = 0.64). These data show that Klinefelter syndrome is associated with long-standing comorbidities that frequently remain under-recognized; a karyotype should be considered in boys with neurocognitive problems.

Background: Several epidemiological studies have demonstrated an increased mortality from cardiovascular causes in patients with Klinefelter Syndrome (KS). Little information is available about the nature of the underlying cardiovascular abnormalities. Aim of the study was to investigate exercise performance, left ventricular architecture and function, vascular reactivity, and carotid intima-media thickness in a group of patients with KS., Materials and Methods: Sixty-nine patients with KS and 48 age-matched controls participated in our population-controlled study. Forty-eight Klinefelter subjects were on testosterone treatment at the time of the investigation while 21 were naive and underwent a complete Doppler echocardiographic examination, a cardiopulmonary exercise test as well as a vascular study including measures of carotid intima-media thickness and endothelial function with flow-mediated dilation of the brachial artery. Patients with KS on testosterone therapy (n=48) were also matched against a population of men with treated secondary hypogonadism (n=21)., Results: Patients with KS exhibited a wide array of cardiovascular abnormalities including left ventricular diastolic dysfunction, reduced maximal oxygen consumption (p<0.01), increased intima-media thickness (p<0.05) (-34% and +42% vs. controls, respectively) and a high prevalence of chronotropic incompetence (55% of patients, p<0.01). No significant difference was found between treated and untreated KS in variance with men treated for secondary hypogonadism., Conclusion: Left ventricular diastolic dysfunction, impaired cardiopulmonary performance, chronotropic incompetence, and increased intima-media thickness suggest that cardiovascular abnormalities are a common finding in KS that is not reversed by testosterone replacement therapy and may represent the pathophysiological underpinnings of the increased risk of dying from heart disease., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Klinefelter syndrome (KS) is the most common sex chromosomal abnormality and is associated with hypergonadotropic hypogonadism as an endocrine disorder. The phenotype is characterized by tall stature, abdominal adiposity and small testicles, and often appears after puberty.We report two cases of SK. The first patient is a 2-year-old boy with short stature who received growth hormone therapy. Because of non-progressive puberty, an evaluation of the reproductive axis was performed, showing increased basal gonadotropins. The karyotype (48 XXYY) confirmed the presence of KS. The second patient is an 8 year-old boy in whom peripheral precocious puberty was suspected. Laboratory tests showed high chorionic gonadotropin levels, and a chest CT scan revealed a mediastinal mass. The karyotype in peripheral blood disclosed a 48 XXYY formula (KS).Short stature does not exclude SK. In patients with a mediastinal mass and neurobehavioral deficits, KS should be suspected., (Copyright © 2012 Asociación Española de Pediatría. Published by Elsevier Espana. All rights reserved.)

Male-factor infertility is the cause of reproductive issues in many couples. For approximately 15% of these men, the origin of the infertility is genetic. These causes include both chromosomal and single-gene disorders frequently impacting spermatogenesis. By identifying the genetic mechanism behind the infertility, we determine the ability of the couple to use assisted reproduction technologies. Use of these methods has ignited a new spectrum of concerns for the genetic competence of the offspring. By knowing what specific genetic risks exist for the offspring of men with these particular disorders, we are able to use preimplantation genetic diagnosis to detect these problems., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Unlabelled: Klinefelter syndrome (KS) is the most frequent chromosomal aneuploidy with a prevalence of 1:500 men but it often remains a largely undiagnosed condition and only 10% of cases are identified in childhood and adolescence. We report the anamnestic, clinical and auxological findings of 14 KS patients diagnosed in paediatric age. 3/14 patients (21%) with KS were diagnosed in prenatal age by amniocentesis, 1 patient was diagnosed at birth due to genital ambiguity and the remaining 10/14 (71.4%) were diagnosed at a chronological age younger than 15 years old for a clinical picture characterized by a peculiar cognitive and behavioral pattern or genital anomalies and abnormalities of pubertal development. The classical karyotype 47 XXY was present in 10/14 subjects (72%), a mosaic form (46 XY/47 XXY) was present in 2/14 (14%) and a complex aneuploidy (48 XXYY and 48 XXXY)was present in the remaining 2/14 (14%) patients. All KS patients diagnosed in childhood and adolescence (10/14 =71.4 %) showed a stature taller than the respective target height and also the predicted final height (calculated from a chronological age older than 7 years old) and the reached final height were significantly taller than target height., Conclusion: according to our retrospective data we can assert that KS in paediatric age is characterized by a stature taller than target

The 48,XXYY syndrome is a rare uncommon gonosome aneuploidy and its incidence is estimated to be 1:18,000-1:40,000. The phenotype associated with this syndrome, classically described as Klinefelter variant, is extremely variable but developmental abnormalities are always present. Ultrasound signs during pregnancy are inconsistent, and only three prenatal cases have been described in the literature. Here, we report a case of 48,XXYY syndrome identified in prenatal period because of the presence of polyhydramnios and bilateral clubfeet on second trimester ultrasound. This observation shows the importance of chromosomal prenatal diagnosis in cases with bilateral clubfeet on morphologic ultrasound. This diagnosis is essential for further characterization of the prenatal phenotype and to improving genetic counselling., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)

Objective: We report a case of a patient with Klinefelter syndrome and glaucoma., Case Presentation: A 30-year-old patient with karyotype 47, XXY, presented with a known medical history of glaucoma. Besides reduced fertility, no characteristic physical or behavioral symptoms for Klinefelter syndrome were found on clinical examination. While both eyes were treated with topical intraocular pressure-lowering medications, an increased intraocular pressure, visual field losses, and advanced optic disc damage with a cup-disc ratio of 0.9 were assessed only in the right eye. However, gonioscopy revealed goniodysgenesis in both eyes., Discussion: Klinefelter syndrome is the most common cause of male hypogonadism with a variety of clinical signs and symptoms. The principal effect is the hypogonadism predisposing to infertility and requiring testosterone replacement therapy. Several other classical features of the syndrome including mental retardation, gynecomastia, and breast cancer are described. However, the association between Klinefelter syndrome and ocular manifestations is rare., Conclusions: : Glaucoma or in fact any other ocular manifestations associated with Klinefelter syndrome are rarely described. Here, we report a case of glaucoma and its treatment combining trabeculotomy and trabeculectomy in a patient with Klinefelter syndrome.

Klinefelter's syndrome, which is characterized by small testes, gynecomastia, hypogonadism, and infertility, is the most common cause of primary testicular failure, and commonly has an XXY karyotype. Deep vein thrombosis and thomboembolic events are a rare occurrence in these patients. Although the exact mechanism is not completely understood, it is thought that increased thromboembolic risk in hypogonadic men can be explained by hypofibrinolysis resulting from androgen deficiency. We present the case of a 48-year-old man with Klinefelter's syndrome who experienced recurrent episodes of deep venous thrombosis and pulmonary embolism while undergoing therapeutic anticoagulation. Our report discusses this association and management of the prothrombotic state in patients with Klinefelter's syndrome.

Background: Klinefelter syndrome (KS) with the karyotype 47,XXY is one of the commonest types of congenital chromosomal disorder in males, with an incidence of 0.1% to 0.2% of newborn male infants. It causes hypogonadism and infertility. Until now, however, only about one-quarter of all persons with KS received the diagnosis during their lifetimes., Methods: Selective review of the literature., Results: KS is caused by aneuploidy of the sex chromosomes. Small, firm testes, the manifestations of androgen deficiency (sparse development of male-pattern body hair, greater than average height, lack of libido, erectile dysfunction) and, in more than 90% of affected men, azoospermia are its main features in adults. Affected boys may have verbalization difficulties and problems with learning and socialization. KS is often accompanied by other disturbances such as gynecomastia, varicose veins, thrombosis, osteoporosis, the metabolic syndrome, type 2 diabetes, and epilepsy. The most important therapeutic measure is testosterone supplementation, which should be initiated if the testosterone concentration drops below 12 nmol/L and should be given as directed in the guidelines for the treatment of hypogonadism. This recommendation is made even though there have not been any randomized controlled trials documenting the efficacy of testosterone therapy in adolescents or young adults. In some cases, viable sperm can be obtained from individual testicular tubules by biopsy, so that these patients are able to become fathers., Conclusion: The diagnosis of KS would be less frequently missed if doctors were more aware of, and attentive to, its key manifestations, particularly the small, firm testes, erectile dysfunction, and the comorbidities mentioned above. If the diagnosis were made more often, patients would more often be able to receive early treatment, which would improve their quality of life.

Study Question: Does the health status of infants fathered by nonmosaic Klinefelter syndrome (KS) patients whose partners underwent ICSI with sperm obtained from testicular dissection reveal any genetic risk for the offspring?., Summary Answer: KS patients undergoing testicular sperm extraction (TESE) are capable of conceiving healthy children., What Is Known Already: Paternity has been successfully achieved in nonmosaic KS patients (47,XXY karyotype) by ICSI using either ejaculated or testicular spermatozoa. A crucial concern is the potential transmission of genetic abnormalities to the offspring. Some studies reported that 47,XXY spermatogonia are capable of completing spermatogenesis leading to the production of mature spermatozoa with increased aneuploidies. Other authors showed that where focal spermatogenesis is present in nonmosaic KS males, it originates from euploid germ cells and, therefore, produces normal mature gametes. In support of this finding, at present, the great majority of children born from nonmosaic KS patients are chromosomally normal., Study Design, Size, Duration: From April 2004 to June 2010, 38 azoospermic patients with nonmosaic KS were examined for the presence of testicular spermatozoa. Spermatozoa were retrieved from 15 patients and 26 ICSI cycles were done (16 with cryopreserved sperm). There were 15 pregnancies leading to the birth of 16 babies who were karyotyped at amniocentesis and after birth., Participants/materials, Setting, Methods: Participants were recruited from couples attending the European Hospital, Rome, and Clinica MAR&Gen, Granada, for infertility treatment. Both the European Hospital and Clinica MAR&Gen are private clinics. Testicular tissue was extracted with TESE or micro-TESE. After retrieval, fresh sperm was used for ICSI or it was cryopreserved for future use., Main Results and the Role of Chance: Spermatozoa were retrieved from 15 patients (14 TESE and 1 micro-TESE) out of 38 (39.5%). A total of 26 ICSI cycles were performed: 10 with fresh and 16 with cryopreserved-thawed sperm. Mean ages (y) of patients with positive and negative sperm retrieval were, respectively, 34.8 ± 1.72 and 35.6 ± 4.08 (NS, nonsignificant). Comparing ICSI cycles performed with fresh sperm (n = 10) to those performed with frozen-thawed sperm (n = 16): Fertilization rates per injected oocyte were 53.0% (44 of 83) and 47.8% (32 of 67), respectively (NS). The cleavage rate per injected oocyte was 90.6% (29 of 32) versus 68.2% (30 of 44); P = 0.026. Clinical outcomes were not significantly different between the fresh and the frozen-thawed sperm group: clinical pregnancy rates were 7 of 10 (70.0%) and 8 of 16 (50.0%); implanted embryos (per transferred embryo) were 8 of 23 (34.8%) and 8 of 29 (27.6%); delivery rates were 6 of 10 (60.0%) and 5 of 16 (31.3%). Sixteen babies were born, all of them are healthy with a normal karyotype, eight from the fresh sperm group and eight from the frozen-thawed sperm group., Limitations, Reasons for Cautions: The small numbers available for study mean that only common problems can be excluded., Wider Implications of the Findings: This study provides further reassurance that KS men can father healthy children and that pre-implantation genetic diagnosis on embryos conceived with their sperm is not strongly indicated. However, until conclusive information is available, such couples should be offered extensive genetic counseling., Study Funding/competing Interest(s): No external funding was obtained for the present study. None of the authors has any conflict of interest to declare., Trial Registration Number: Not applicable.

47, XXY or Klinefelter syndrome (KS), the most common chromosomal aberration in males, is characterized by either absolute or relative hypogonadism with frequent decline in serum testosterone (T) following the onset of puberty. Decreased T levels are the result of testicular dysfunction with decrease in size of Leydig cells, and loss of germs and Sertoli cells leading to tubular hyalinization. Increase in estradiol results from over-expression of aromatase CYP19. Deficient androgen production and observed varied response of end-organs to T leads to delayed progression of puberty with decreased facial/body hair, poor muscle development, osteoporosis, and gynecomastia. It is possible that hypogonadism and excessive estradiol production contribute to emotional and social immaturity, and specific learning disabilities in KS. Based on the authors' experience and literature review, early fertility preservation and hormonal supplementation may normalize pubertal development, prevent metabolic sequelae of hypogonadism, and have a positive effect on academic and social development. No randomized clinical trials are available studying the effects of T supplementation on reproductive or cognitive issues in KS. Aggressive T supplementation (topical gel) and selective use of aromatase inhibitors may be considered at the onset of puberty with careful follow-up and titration to reach age-specific high-normal physiologic serum values. The decision to institute hormonal therapy should be part of a multidisciplinary approach including physical, speech, behavioral, and occupational therapy. © 2013 Wiley Periodicals, Inc., (Copyright © 2013 Wiley Periodicals, Inc.)

The developing brain is highly sensitive to the organizing effects of steroids of gonadal origin in a process referred to as sexual differentiation. Early hormone effects prime the brain for adult sensitivity to the appropriate hormonal milieu, maximizing reproductive fitness via coordinated physiology and behavior. Animal models, in particular rodents, have provided insight into general principles and the cellular and molecular mechanisms of brain differentiation. Cellular endpoints influenced by steroids in the developing brain include neurogenesis, migration, apoptosis, dendritic growth, and synaptic patterning. Important roles for prostaglandins, endocanabinoids, and epigenetics are among the many cellular mediators of hormonal organization. Transference of general principles of brain sexual differentiation to humans relies on observations of individuals with genetic anomalies that either increase or decrease hormone exposure and sensitivity. The physiology and behavior of individuals with XXY (Klinefelter syndrome) has not been considered in the context of sexual differentiation of the brain, most likely due to the delay in diagnoses and highly variable presentation. The behavioral phenotype and impairments in the domains of speech and language that are characteristic of individuals with XXY is consistent with the reduced androgen production associated with the syndrome. Hormone replacement appears effective in restoring some deficits and impact may be further improved by increased understanding of the hormonally mediated sexual differentiation of the brain., (Copyright © 2013 Wiley Periodicals, Inc.)

47,XXY/Klinefelter syndrome is the most common sex chromosomal aneuploidy, yet 64% of males with this condition go undiagnosed. 48,XXYY is less common and there is less known about the diagnosis. The objective of this study is to describe the diagnosis experiences of parents of males with 47,XXY and 48,XXYY. Parents of 89 males with 47,XXY and 76 males with 48,XXYY completed a survey that gathered data about their experiences leading to a diagnosis, including the current age of the child, age at diagnosis, reasons for initial concern, and the specialists providing the diagnosis. In the 47,XXY cohort diagnosed postnatally, 59% presented with developmental delay, with a mean age at first parental concern of 5.2 years and mean age of diagnosis at 10.0 years. The remaining 41% presented with endocrinologic issues with a mean age at first concern of 19.1 years and mean age of diagnosis at 21.1 years. In the 48,XXYY group, 93% presented with developmental delay, with mean age at first parental concern of 2.4 years and mean age of diagnosis at 7.6 years. Hence, the average time from initial parental concern to diagnosis of 47,XXY or 48,XXYY ranges from 2 to 5 years, with those presenting with developmental issues having a longer lag to diagnosis compared to those presenting with endocrinologic issues. Increased awareness of the developmental, psychological, and medical features of 47,XXY and 48,XXYY is important to facilitate timely diagnosis and initiation of appropriate screenings and treatments that are important for optimal outcomes., (Copyright © 2013 Wiley Periodicals, Inc.)

Context: Recently, new clinically important information regarding Klinefelter syndrome (KS) has been published. We review aspects of epidemiology, endocrinology, metabolism, body composition, and neuropsychology with reference to recent genetic discoveries., Evidence Acquisition: PubMed was searched for "Klinefelter," "Klinefelter's," and "XXY" in titles and abstracts. Relevant papers were obtained and reviewed, as well as other articles selected by the authors., Evidence Synthesis: KS is the most common sex chromosome disorder in males, affecting one in 660 men. The genetic background is the extra X-chromosome, which may be inherited from either parent. Most genes from the extra X undergo inactivation, but some escape and serve as the putative genetic cause of the syndrome. KS is severely underdiagnosed or is diagnosed late in life, roughly 25% are diagnosed, and the mean age of diagnosis is in the mid-30s. KS is associated with an increased morbidity resulting in loss of approximately 2 yr in life span with an increased mortality from many different diseases. The key findings in KS are small testes, hypergonadotropic hypogonadism, and cognitive impairment. The hypogonadism may lead to changes in body composition and a risk of developing metabolic syndrome and type 2 diabetes. The cognitive impairment is mainly in the area of language processing. Boys with KS are often in need of speech therapy, and many suffer from learning disability and may benefit from special education. Medical treatment is mainly testosterone replacement therapy to alleviate acute and long-term consequences of hypogonadism as well as treating or preventing the frequent comorbidity., Conclusions: More emphasis should be placed on increasing the rate of diagnosis and generating evidence for timing and dose of testosterone replacement. Treatment of KS should be a multidisciplinary task including pediatricians, speech therapists, general practitioners, psychologists, infertility specialists, urologists, and endocrinologists.

Klinefelter syndrome is one of the most frequent sex chromosomal aberration. It is usually not recognized before puberty and many patients remain never diagnosed. Delayed puberty and hypergonadotropic hypogonadism are typical in this syndrome. Early diagnosis and therapy with androgens is important for patients. We present case of 8-year old boy with Klinefelter syndrome who was admitted to our department because of precocious puberty.

Objective: Coexistence of Klinefelter syndrome and holoprosencephaly (HPE) is rare. We report alobar HPE, cebocephaly, and micropenis in a Klinefelter fetus of a mother with type 2 diabetes mellitus with obesity and poor metabolic control., Case Report: A 38-year-old woman was referred for therapy of type 2 diabetes mellitus with poor glycemic control at 24 weeks of gestation. On examination, she had a body height of 162 cm and a body weight of 105 kg. She had been treated with oral medication for diabetes mellitus for 4 years with poor maternal metabolic control. She had prominent glucosuria and glycemia. Her hemoglobin A1c was 7.5% (normal range: 3.4-6.1%), and the fasting glucose level was 141 mg/mL (normal range: 70-99 mg/mL) during this visit. Her husband was 46 years old. Prenatal ultrasound revealed a singleton fetus with fetal biometry equivalent to 24 weeks, alobar HPE, cebocephaly, and micropenis. As a result of poor maternal heath and fetal anomaly, the parents elected to terminate the pregnancy, and a 986-g male fetus was delivered with hypotelorism, HPE, cebocephaly, micropenis, and cryptorchidism. Cytogenetic analysis of the cord blood revealed a karyotype of 47,XXY. The parental karyotypes were normal. Polymorphic DNA analysis revealed a paternal origin of the extra X chromosome. Molecular analysis of the HPE genes of SHH, ZIC2, SIX3, and TGIF revealed no mutations., Conclusion: Prenatal diagnosis of HPE should include a biochemical examination to identify metabolic factors such as maternal diabetes, and preventive management should be considered in subsequent pregnancies to achieve good control of maternal diabetes., (Copyright © 2012. Published by Elsevier B.V.)

A 31-year-old Caucasian male was referred for panhypopituitarism resulting from a surgically removed craniopharyngioma. The patient had been previously submitted to kidney transplantation for end-stage renal disease from X-linked Alport syndrome (ATS). Subsequent quantitative fluorescent polymerase chain reaction analysis indicated a 47,XXY karyotype consistent with Klinefelter syndrome (KS). The relevance of this unique case stems from several issues: 1) KS was an unexpected finding because of a previous diagnosis of hypogonadotropic hypogonadism resulting from craniopharyngioma; 2) the discovery of a de novo p.G406S substitution causing ATS; and 3) the multifactor origin of severe sexual dysfunction. This is the first description of the co-occurrence of KS, ATS, and craniopharyngioma.

Klinefelter syndrome (KS) remains the most common, yet often undiagnosed, chromosomal aberration in men. Early diagnosis and treatment can improve the health of patients with KS. The aim of this study was to evaluate the inactivation pattern of supernumerary X chromosomes. The secondary aim was to design a reliable and cost-effective molecular test for detection of X chromosome disomy. Methylation-specific polymerase chain reaction (M-PCR), with primers for familial mental retardation (FMR1) and X chromosome inactive-specific transcript (XIST) genes, was used to detect the presence of X chromosome disomy in men. Seventeen fertile males, 12 females, and 35 males with KS (28 with 47,XXY karyotype, and 7 with 47,XXY/46,XY mosaics) were included in the study. Results of the karyotype were compared with the results of semiquantitative M-PCR. Inactivation of X chromosomes was measured by XIST/FMR-1 methylation ratio. Differences in the methylation patterns of FMR1 and XIST genes between 46,XY men and men with X chromosome disomy allowed for rapid detection of the presence of an additional X chromosome, achieving 100% sensitivity and specificity using M-PCR. The methylated:unmethylated FMR1 amplicon ratio allowed the detection of 1 additional X chromosome per 100 normal XY cells (1% of XX/XY mosaicism). In our series, 50% of 47,XXY men showed skewed inactivation of the X chromosome. Men with KS can have incomplete inactivation of supernumerary X chromosomes. M-PCR is a sensitive, specific, fast, and relatively inexpensive test for the diagnosis of X chromosome disomy.

Klinefelter syndrome (KS) with the classic 47,XXY karyotype is the most frequent chromosomal aneuploidy, with a prevalence of 1 in 700 men; although the classic clinical picture is well-known and easily recognizable, most patients remain undiagnosed. The rate of diagnosis during childhood is extremely low, and only 10% of cases are identified before puberty, with a subsequent rate of ascertainment during lifetime of 25%. The low rate of timely diagnosis is because most of the classical signs and symptoms of androgen deficiency appear in mid- to late adolescence but it is important to recognize that adult men with KS may show a great variability in clinical and physical features. A common, often underappreciated, element in young boys and children with KS is the characteristic cognitive and behavioral pattern. We describe 2 patients who were diagnosed at 7.1 and 10 years through a characteristic neurocognitive profile. Both of them showed low-normal scores when evaluated by tests of general intelligence and a behavioral profile characterized by immaturity, low self-esteem, and learning disabilities. Clinical examination showed tall stature and progressive growth acceleration between 5 and 7 years, and one of them had hypoplastic scrotum with monolateral cryptorchidism. To achieve the goal of an early diagnosis of KS, it is necessary to increase medical awareness of the disease and, in particular, to augment pediatricians' knowledge that during prepubertal age pathognomonic clinical features of KS are often lacking but a characteristic cognitive and behavioral pattern is commonly present.